Peptide derivatives and medicinal compositions

ABSTRACT

The present invention to novel nociceptin receptor agonists which are peptide derivatives represented by the following general formula (1): 
     
       
         
         
             
             
         
       
         
         
           
             (in which A is alkylene, —CH 2 ) n CO— or a group expressed by the following formula (2) or (3): 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             wherein n represents an integer of 1 to 8; X and Y are same or different and each represents —CONH— or —CH 2 NH—; R 1 , R 2  and R 3  are same or different and each represents alkyl, aryl or heteroaryl; Z represents —CON(R 4 )R 5  or —CH 2 N(R 4 )R 5 ; R 4  and R 5  are same or different and each represents hydrogen, alkyl, aryl or heteroaryl) or a pharmaceutically acceptable salt thereof. A pharmaceutical composition according to the present invention is useful as a nociceptin receptor agonist.

TECHNICAL FIELD

The present invention relates to a novel peptide derivative useful as apharmaceutical or a pharmaceutically acceptable salt thereof, and apharmaceutical composition containing the same as an active ingredient.

BACKGROUND ART

There are used, as an analgesic, a narcotic analgesic (morphine and thelike), a non-narcotic analgesic (aspirin, indomethacin and the like) anda narcotic-antagonistic analgesic (pentazocine and the like). A narcoticanalgesic exerts its analgesic effect by inhibiting an algesicexcitation transmission mainly in a central system. A non-narcoticanalgesic exerts its analgesic effect by inhibiting the production of adorologenic substance mainly in a peripheral system. Anarcotic-antagonistic analgesic exerts its analgesic effect by amechanism similar to that of a narcotic analgesic.

Nevertheless, there are no useful analgesics against a chronic painwhich cannot be suppressed by a morphine, an allodynia associated withherpes zoster or a hyperalgesia, and an excellent analgesic has beenstill demanded.

Recently, an opioid receptor such as mu (μ), delta (δ) or kappa (κ)opioid receptor was identified, and a further novel subtype receptor,namely, nociceptin receptor (ORL-1) was identified while its intrinsicagonist nociceptin was also found. The nociceptin receptor (ORL-1)agonist is suggested to be effective in treating a neural inflammation,and this agonist is a highly effective analgesic which has lesspsychological side effects and causes less indulgence.

DISCLOSURE OF THE INVENTION

The present inventors searched for a compound having an effect on thenociceptin receptor (ORL-1) and finally found that a peptide derivativeexpressed by the following general formula (1) or a pharmaceuticallyacceptable salt is an agonist of the nociceptin receptor (ORL-1) and hasa potent analgesic effect, thereby establishing the present invention.It was also found that a compound of the present invention is useful asan analgesic or as an anxiolytic agent.

A peptide derivative according to the present invention is expressed bygeneral formula (1):

in which A is alkylene, —(CH₂)_(n)CO— or a group by formula (2) or (3):

X and Y are same or different and each represents —CONH— or —CH₂NH—;

R¹, R² and R³ are same or different and each represents alkyl, aryl orheteroaryl, such alkyl, aryl and heteroaryl being optionally substitutedby 1 to 3 same or different substituents selected from a groupconsisting of halogen, nitro, hydroxy, carboxy, cyano, carbamoyl, alkyl,aryl (optionally substituted by hydroxy), heteroaryl (optionallysubstituted by hydroxy), alkenyl, alkynyl, alkoxycarbonyl, acyl, amino,monoalkylamino, dialkylamino, alkoxy, aryloxy, arylalkyloxy, alkylthio,arylalkylthio, heteroarylalkylthio, arylsulfonyl, alkylsulfonyl andguanidino;

Z represents —CON(R⁴)R⁵ or —CH₂N(R⁴)R⁵ wherein R⁴ and R⁵ are same ordifferent and each represents hydrogen, alkyl, aryl or heteroaryl, suchalkyl, aryl and heteroaryl being optionally substituted by 1 to 3 sameor different substituents selected from a group consisting of halogen,nitro, hydroxy, carboxy, cyano, carbamoyl, alkyl, aryl (optionallysubstituted by hydroxy), heteroaryl (optionally substituted by hydroxy),alkenyl, alkynyl, alkoxycarbonyl, acyl, amino, monoalkylamino,dialkylamio, alkoxy, aryloxy, arylalkyloxy, alkylthio, arylalkylthio,heteroarylalkylthio, arylsulfonyl, alkylsulfonyl, guanidino,N-monoalkylcarbamoyl (alkyl is optionally substituted),N,N-dialkylcarbamoyl (alkyl is optionally substituted with halogen,nitro, hydroxy, carboxy, cyano, carbamoyl, alkyl and aryl) andhydroxymethyl (methyl is optionally substituted by halogen, nitro,hydroxy, carboxy, cyano, carbamoyl, alkyl and aryl).

In the present invention, examples of “alkyl” may include a group of astraight or branched chain having 1 to 6 carbon atoms such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl and n-hexyl.

In the present invention, examples of “aryl” may include a group having6 to 12 carbon atoms such as phenyl and naphthyl.

In the present invention, examples of “heteroaryl” may include a 5 to6-membered ring having 1 to 4 nitrogen, oxygen or sulfur atoms or afused ring thereof with a benzene ring, such as pyrrolyl, furyl,thienyl, imidazolyl, pyrazolyl, pyridyl, indoryl, benzofuryl,benzoimidazolyl, benzothienyl, quinolyl and isoquinolyl.

In the present invention, examples of “halogen” may include fluorine,chlorine, bromine and iodine.

In the present invention, examples of “alkenyl” may include a group of astraight or branched chain having 2 to 3 carbon atoms such as vinyl,propenyl and isopropenyl.

In the present invention, examples of “alkynyl” may include a chainhaving 2 to 3 carbon atoms such as ethynyl and propargyl.

In the present invention, examples of each alkyl moiety in“alkoxycarbonyl”, “monoalkylamino”, “dialkylamino”, “alkoxy”,“arylalkyloxy”, “alkylthio”, “arylalkylthio”, “heteroarylalkylthio”,“alkylsulfonyl”, “N-monoalkylcarbamoyl” and “N,N-dialkylcarbamoyl” mayinclude the above described alkyl.

In the present invention, examples of each aryl moiety in “aryloxy”,“arylalkyloxy”, “arylalkylthio” and “arylsulfonyl” may include the abovedescribed aryl.

In the present invention, examples of each heteroaryl moiety in“heteroarylalkylthio” may include the above described heteroaryl.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1 and 2 show reaction sequences for preparing compounds of thisinvention.

A compound (1) of the present invention can be produced by the followingmethod [1] (see FIG. 1 or [2] (see FIG. 2):

Wherein, in FIG. 1, R¹ to R⁵ and n are defined as described above; Raand Rc represents protective groups for amino groups and Rb represents aprotective group.

As shown in FIG. 1, amino acid derivates (11) and (12) are reacted inthe presence of a suitable condensing agent to obtain a compound (13),which is then subjected to the deprotection of the protective group foran amino group and fused with an amino derivative (15), and thereaftersubjected again to the deprotection of the protective group for an aminogroup, thereby obtaining an amino compound (16). This is then reactedwith an aldehyde (17), and then treated with a reducing agent to obtaina compound (18). After cleaving the protective group Rb for a carboxylgroup followed by a reaction with an amino compound (19) in the presentof a suitable condensing agent, a compound (20) is obtained. By cleavingall of the protective groups for amino groups and the like, a moiety ofa compound (1) of the present invention wherein A is alkylene, and X andY are —CONH— can be obtained.

Examples of the condensing agent employed in each of the above describedproduction method or the condensation method may include a methodemploying N,N′-dicyclohexylcarbodiimide (hereinafter abbreviated as“DCC”), a method employing DCC and 1-hydroxybenzotriazole, a methodemploying 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and1-hydroxybenzotriazole, a method employing 1,1′-carbonyldiimidazole or amethod employing isobutyl chloroformate or diphenylphosphoryl azide inthe presence of triethylamine and the like.

Examples of the reducing agent employed in each of the above describedproduction methods may include a metal hydride compound such as sodiumcyanoborohydride, sodium borohydride and lithium aluminum hydride or adimethylamine-borane complex.

Examples of the protective group for the amino group employed in each ofthe above described production methods may include benzyloxycarbonyl,tert-butoxycarbonyl, formyl, trityl, chloroacetyl, trialkylsilyl, benzyland 9-fluorenylmethoxycarbonyl. Examples of the protective group for thecarboxyl group may include methyl, ethyl, benzyl and phenacyl.

Examples of the protective group for the amino acid side chain of theamino acid derivative employed in each of the above described productionmethod, for example in the case of arginine, may include a4-methoxy-2,3,6-trimethlbenzenesulfonyl group (Mtr), a2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl group (Pmc) andtert-butoxycarbonyl, while that in the case of tyrosine may includetert-butyl and benzyl.

The above described protective groups can be introduced and cleaved by astandard method, for example, by a method described in a reference (T.W. Greene, et al., “Protective Groups in Organic Synthesis”, John Wiley& Sons, Inc., New York, 1999, p. 17–292, p. 369–653, p701–747).

There are used, as a solvent for a condensation reaction or for theintroduction or cleavage of a protective group in the above describedproduction method, absolute or hydrated alcohols, organic acids, esters,halogenated hydrocarbons, ketones and aprotic polar solvents or amixture solvent thereof.

Examples of the absolute or hydrated alcohols may include absolute orhydrated methanol, absolute or hydrated ethanol and the like, examplesof the organic acids may include acetic acid, trifluoroacetic acid andthe like, examples of the esters may include ethyl acetate, methylacetate and the like, examples of the ethers may include diisopropylether, diethyl ether, tetrahydrofuran and the like, examples of thehalogenated hydrocarbons may include dichloromethane, dichloroethane,chloroform and the like, examples of the ketones may include acetone,ethyl methyl ketone and the like, and examples of the aprotic polarsolvents may include dimethyl sulfoxide, N,N′-dimethyl formamide and thelike.

The reaction temperature in each production method is −20 to 100° C.,preferably 0 to 50° C., more preferably 10 to 30° C. The reactiontemperature in deprotecting a protective group is −10 to 80° C.,preferably 0 to 50° C., more preferably 5 to 20° C.

In FIG. 2, R¹ to R⁵ are defined as described above; and Ra and Rcrepresents protective groups for amino groups.

As shown in FIG. 2, an amino acid derivative (21) and an amino compound(19) are reacted in the presence of a suitable condensing agent toobtain a compound (22), which is then subjected to the deprotection ofthe protective group for an amino group and fused with an amino acidderivative (11), and thereafter subjected again to the deprotection ofthe protective group for an amino group, followed by the condensationwith an amino acid derivative (15) followed again by the deprotection ofthe protective group for an amino group, thereby obtaining an aminocompound (25). This is then reacted with an aldehyde (17), and thentreated with a reducing agent to obtain a compound (20). Then, bycleaving all of the protective groups for amino groups and the like, amoiety of a compound (1) of the present invention wherein A is alkylene,and X and Y are —CONH— can be obtained.

The reaction in each step can be performed as described above.

The compound of the present invention or its salt thus produced may bepurified into a free base form, free acid form, acid addition salt form,metal salt form, d form, l form or dl mixture form by a method known perse such as condensation, liquid phase conversion, partition, solventextraction, crystallization, fractionation, chromatography and the like.

When the compound according to the present invention is administered asa pharmaceutical, the compound of general formula (1) or its salt may begiven as it is or in a pharmaceutical composition containing it at aconcentration of 0.1 to 99.5%, preferably 0.5 to 90% in apharmaceutically acceptable non-toxic inert carrier.

As the carrier, there is used at least one of solid, semi-solid orliquid diluent, filler and other auxiliary agents in the formulation.The compound expressed by general formula (1) or its salt is givenpreferably as a unit dosage form. While the compound expressed bygeneral formula (1) or its salt can exert its effect when given orally,it can exert its effect also when given by an intra-tissueadministration (such as intravenous injection), topical administration(percutaneous administration, instillation, nasal administration) orrectal administration.

While the dosage of the compound according to the present invention as apharmaceutical may be adjusted preferably with taking the age, bodyweight condition of the patient, administration route, nature and degreeof the disease into consideration, it is usually 0.1 to 1000 mg daily asthe compound according to the present invention in adult, preferably 1to 500 mg. A more or less dosage may sometimes be required. The numberof dosage may be divided into 2 to 3 times in a day.

The oral administration can be accomplished in the form of powder,tablet, capsule, sugar-coated tablet, granule, dust, suspension, liquid,syrup, drop, buccal formulation or other formulations.

The powder formulation can be produced by pulverizing the compoundexpressed by general formula (1) or the salt thereof into particleshaving suitable sizes.

The dust formulation can be produced by pulverizing the compoundexpressed by general formula (1) or the salt thereof into particleshaving suitable sizes followed by mixing with a similarly pulverizedpharmaceutical carrier, for example an edible carbohydrate such asstarch, mannitol and the like. If necessary, other additives such asseasonings, preservatives, dispersing agents, colorants and flavors mayalso be added.

The tablet formulation can be produced by preparing a powder mixturecontaining an excipient, granulating or slugging, adding a disintegrantor lubricant and then compacting into tablets.

The powder mixture is prepared by mixing a suitably pulverized compoundwith the above described diluent or base if necessary together withbinders (for example, sodium carboxymethyl cellulose, methyl cellulose,hydroxypropylmethyl cellulose, gelatin, polyvinyl pyrrolidone, polyvinylalcohol and the like), dissolution retardants (for example, paraffin andthe like), adsorbents (for example, bentonite, kaolin, dicalciumphosphate and the like).

A powder mixture is first made wet using a binder such as a syrup,starch, gum arabic, cellulose solution or a polymer solution, and thenagitated and mixed, dried and pulverized to obtain a granule.

Instead of granulating a powder, a compacting machine is used first toobtain an incompletely shaped slug, which is then pulverized to obtain agranule. The granule thus obtained can be made free of adhesion to eachother by adding stearic acid, stearates, talc, mineral oil and the likeas a lubricant. The plane tablet thus obtained may be film-coated orsugar-coated.

The compound expressed by general formula (1) or its salt can also becompacted directly after mixing with a flowable inert carrier. Atransparent or opaque protective film formed as a closely coveringshellac coating, a sugar or polymeric film and a glossy film of a waxmay also be employed.

A capsule formulation can be produced by filling a powder, dust orgranule formulation for example in an encapsulating shell such as agelatin capsule. The compaction may be accomplished also after mixingthe powdery material with a lubricant or fluidizing agent such ascolloidal silica, talc, magnesium stearate, calcium stearate, solidpolyethylene glycol and the like. The efficacy of a pharmaceutical afterthe ingestion of a capsule formulation can be enhanced by adding adisintegrant or solubilizing agent such as carboxymethyl cellulose,calcium carboxymethyl cellulose, low-substituted hydroxypropylcellulose, calcium croscarmellose, sodium carboxymethyl starch, calciumcarbonate, sodium carbonate and the like. A compound expressed bygeneral formula (1) or its salt may be suspended and dispersed in avegetable oil, polyethylene glycol, glycerin or surfactant and thenencapsulated in a gelatin sheet to obtain a soft capsule formulation.

Other oral formulations such as solutions, syrups, troches, elixirs andnasal formulations may be presented as a unit dosage form containing acertain amount of a compound expressed by general formula (1) or a saltthereof. For producing an ointment, fats, oils, lanolin, petrolatum,paraffin, wax, resins, plastics, glycols, higher alcohols, glycerin,water, emulsifier, suspending agent or other suitable additives areemployed as starting material or bases, to which a compound expressed bygeneral formula (1) or its salt is added and mixed. A poulticeformulation can be produced by mixing a powder of a compound expressedby general formula (1) or a salt thereof with a suitable liquid materialsuch as glycerin, water and the like followed by adding an essential oilcomponent. For producing a plaster formulation, fats, oils, fatty acidsalts, wax, resins, plastics, purified lanolin, rubber or a mixturethereof are employed as starting material or bases, to which a compoundexpressed by general formula (1) or its salt is admixed uniformly. Aneye drop formulation can be produced by dissolving or suspending acertain amount of a compound expressed by general formula (1) or a saltthereof in sterilized purified water, physiological saline or distilledwater for injection to make a certain volume.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in detail with reference to thefollowing Examples and Test Examples according to the present invention.

EXAMPLE 1N-α-6-Guanidinohexyl-L-tyrosyl-L-tyrosyl-L-arginyl-L-tryptophanamide(SEQ. ID. NO 2)

Step 1

N-ω-(2,2,5,7,8-Pentamethylchroman-6-sulfonyl)-L-arginyl-L-tryptophanamide

N-α-9-fluorenylmethoxycarbonyl-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-arginine(2.0 g, 3.0 mmol) was dissolved in DMF (15 mL), combined with1-hydroxybenzotriazole (449 mg, 3.3 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC; 636mg, 3.3 mmol) and stirred at room temperature for 10 minutes. This wascooled to 0° C., L-tryptophanamide hydrochloride (723 mg, 3.0 mmol) andN,N-diisopropylethylamine (0.53 mL) were added, and the mixture wasstirred further at room temperature overnight. The reaction solution wasextracted with ethyl acetate, washed with a saturated aqueous solutionof sodium hydrogen carbonate, saturated brine and water. The organiclayer was dried over sodium sulfate, filtered through a cotton plug toremove solids, and washed with ethyl acetate. The filtrate and the washwere combined and concentrated under reduced pressure. The resultantsyrup was combined with a 10% piperidine/DMF solution (30 mL) todissolve, and stirred at room temperature for 20 minutes. The reactionsolution was concentrated under reduced pressure, and the resultantresidue was subjected to column chromatography to obtainN-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-arginyl-L-tryptophanamide(compound 1; yield: 1.8 g).

Step 2

O-tert-Butyl-L-tyrosyl-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-arginyl-L-tryptophanamide

N-α-9-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine (1.4 g, 3.0 mmol)and the compound 1 (1.8 g, 2.9 mmol) were reacted in accordance with themethod for synthesizing the compound 1 to obtainO-tert-butyl-L-tyrosyl-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-arginyl-L-tryptophanamide(compound 2; yield: 2.4 g).

Step 3

O-tert-Butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-arginyl-L-tryptophanamide

N-α-9-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine (674 mg, 1.5mmol) and the compound 2 (1.2 g, 1.4 mmol) were reacted in accordancewith the method for synthesizing the compound 1 to obtainO-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-arginyl-L-tryptophanamide(compound 3; yield: 1.3 g).

Step 4

6-(2,3-di-tert-Butoxycarbonyl)guanidino-1-hexanol

6-Amino-1-hexanol (1.2 g, 10.2 mmol) was dissolved in methylene chloride(10 mL), combined with1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (3.97 g, 13.7mmol) and stirred overnight. The reaction solution was concentratedunder reduced pressure, and the residue was subjected to a columnchromatography to obtain6-(2,3-di-tert-butoxycarbonyl)guanidino-1-hexanol (compound 4; yield:3.5 g)

Step 5

6-(2,3-di-tert-Butoxycarbonyl)guanidino-1-hexanal

The compound 4 (169 mg, 0.47 mmol) was dissolved in methylene chloride(5 mL), combined with Dess-Martin reagent (700 mg, 1.7 mmol) and stirredfor 15 minutes. After completion of the reaction, the reaction solutionwas combined with a saturated aqueous solution of sodium hydrogencarbonate and an aqueous solution of sodium thiosulfate, stirred for 15minutes, and extracted with ether. The organic layer was dried oversodium sulfate, made free of solids by filtration through a cotton plug,and then washed with ether. The filtrate and the wash were combined andconcentrated under reduced pressure to obtain a crude6-(2,3-di-tert-butoxycarbonyl)guanidino-1-hexanal (compound 5)(166 mg).

Step 6

N-α-6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl-(O-tert-butyl)-L-tyrosyl-(O-tert-butyl)-L-tyrosyl-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-arginyl-L-tryptophanamide(SEQ. ID. NO. 1)

The compound 3 (250 mg, 0.23 mmol) and a crude product of the compound 5(166 mg) were dissolved in methanol (3.5 mL), adjusted at pH4 withacetic acid, and stirred at room temperature for 15 minutes. Thereaction solution was cooled to 0° C., combined with sodiumcyanoborohydride (59.2 mg, 0.94 mmol), and stirred at room temperaturefurther for 30 minutes. After completion of the reaction, the reactionsolution was concentrated under reduced pressure, and the resultantresidue was extracted with ethyl acetate, and the organic layer washedwith a saturated aqueous solution of sodium hydrogen carbonate, asaturated brine and water. The organic layer was dried over sodiumsulfate, made free of solids by filtration through a cotton plug, andwashed with ethyl acetate. The filtrate and the wash were combined andconcentrated under reduced pressure, and the resultant residue wassubjected to a column chromatography to obtainN-α-6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl-(O-tert-butyl)-L-tyrosyl-(O-tert-butyl)-L-tyrosyl-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-arginyl-L-tryptophanamide(compound 6; yield: 174 mg).

Step 7

N-α-6-Guanidinohexyl-L-tyrosyl-L-tyrosyl-L-arginyl-L-tryptophanamide(SEQ. ID. NO 2)

The compound 6 (350 mg, 0.25 mmol) was dissolved in a mixture oftrifluoroacetic acid (12 mL), phenol (900 mg), ethanedithiol (0.3 mL),thioanisole (0.6 mL) and water (0.6 mL), and stirred at room temperaturefor 2 hours. After completion of the reaction, the reaction solution waspoured into ether, and subjected to a centrifuge to obtain a pellet.

This was subjected to a high pressure liquid column chromatography toobtainN-α-6-guanidinohexyl-L-tyrosyl-L-tyrosyl-L-arginyl-L-tryptophanamide(compound 7; 160 mg, 78%).

FAB MS [M+H]⁺=827

EXAMPLE 2N-α-4-Guanidinobutyryl-L-tyrosyl-L-tyrosyl-L-arginyl-L-tryptophanamide(SEQ. ID. NO 2)

Step 1

4-(2,3-di-tert-Butoxycarbonylguanidino)butyric acid

4-Aminobutyric acid (100 mg, 0.97 mmol) was dissolved in tetrahydrofuran(0.3 mL) and water (0.03 mL), combined with1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (340 mg, 1.2mmol) and stirred at 60° C. overnight. The reaction solution wasconcentrated under reduced pressure, and the residue was subjected to acolumn chromatography to obtain4-(2,3-di-tert-butoxycarbonylguanidino)butyric acid (compound 8; yield:181 mg).

Step 2

N-α-[4-(2,3-di-tert-Butoxycarbonyl)guanidinobutyryl]-(O-tert-butyl)-L-tyrosyl-(O-tert-butyl)-L-tyrosyl-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-arginyl-L-tryptophanamide(SEQ. ID. NO. 1)

The compound 3 (200 mg, 0.19 mmol) and the compound 8 (84.4 mg, 0.24mmol) were reacted in accordance with the method for synthesizing thecompound 1 to obtainN-α-[4-(2,3-di-tert-butoxycarbonyl)guanidinobutyryl]-(O-tert-butyl)-L-tyrosyl-(O-tert-butyl)-L-tyrosyl-[N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)]-L-arginyl-L-tryptophanamide(compound 9; yield: 212 mg).

Step 3

N-α-4-Guanidinobutyryl-L-tyrosyl-L-tyrosyl-L-arginyl-L-tryptophanamide(SEQ. ID. NO 2)

The compound 9 (100 mg, 0.07 mmol) was reacted in accordance with themethod for synthesizing the compound 7 to obtainN-α-4-guanidinobutyryl-L-tyrosyl-L-tyrosyl-L-arginyl-L-tryptophanamide(compound 10; yield: 42 mg).

FAB MS [M+H]⁺=813

EXAMPLE 3N-α-6-Guanidinohexyl-L-tyrosyl]-N-[5-amino-(S)-1-[[N-2-(3-indolyl)ethyl]aminomethyl]pentyl]-L-tyrosinamide(SEQ. ID. NO 2)

Step 1

N-9-Fluorenylmethoxycarbonyl-N-ε-tert-butoxycarbonyl-lysinal

N-9-fluorenylmethoxycarbonyl-N-ε-tert-butoxycarbonyl-lysinol (200 mg,0.44 mmol) was dissolved in methylene chloride (5 mL), combined withDess-Martin reagent (746 mg, 1.8 mmol) and stirred at room temperaturefor 15 minutes. After completion of the reaction, the reaction solutionwas combined with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium thiosulfate,stirred for 15 minutes, and then extracted with ether. The organic layerwas dried over sodium sulfate, made free of solids by filtration througha cotton plug, and then washed with ether. The filtrate and the washwere combined and concentrated under reduced pressure to obtain a crudeproduct of N-9-fluorenylmethoxycarbonyl-N-ε-tert-butoxycarbonyl-lysinal(compound 11) (199 mg).

Step 2

6-(N-tert-Butoxycarbonyl)amino-(S)-2-(N-9-fluorenylmethoxycarbonyl)amino-N-[2-(3-indolyl)ethyl]hexylamine

Tryptamine (198 mg, 1.2 mmol) and a crude product of the compound 11(279 mg, 0.62 mmol) were dissolved in methanol (12 mL), adjusted at pH4with acetic acid, and then stirred at room temperature for 15 minutes.The reaction solution was cooled to 0° C., combined with sodiumcyanoborohydride (200 mg, 3.2 mmol) and stirred further at roomtemperature overnight. After completion of the reaction, the reactionsolution was concentrated under reduced pressure, the resultant residuewas extracted with ethyl acetate, and the organic layer washed with asaturated aqueous solution of sodium hydrogen carbonate, saturated brineand water. The organic layer was dried over sodium sulfate, made free ofsolids by filtration through a cotton plug, and washed with ethylacetate. The filtrate and the wash were combined and concentrated underreduced pressure, and the resultant residue was subjected to a columnchromatography to obtain6-(N-tert-butoxycarbonyl)amino-(S)-2-(N-9-fluorenylmethoxycarbonyl)amino-N-[2-(3-indolyl)ethyl]hexylamine(compound 12; yield: 250 mg).

Step 3

6-(N-tert-Butoxycarbonyl)amino-(S)-2-(N-9-fluorenylmethoxycarbonyl)amino-N-butoxycarbonyl-N-[2-(3-indolyl)ethyl]hexylamine

The compound 12 (250 mg, 0.42 mmol) was dissolved in methylene chloride(6 mL), cooled to 0° C., combined with di-tert-butyl dicarbonate (110mg, 0.50 mmol) and triethylamine (0.1 mL), and then stirred further atroom temperature for 30 minutes. After completion of the reaction, thereaction solution was concentrated under reduced pressure, the resultantresidue was subjected to a column chromatography to obtain6-(N-tert-butoxycarbonyl)amino-(S)-2-(N-9-fluorenylmethoxycarbonyl)amino-N-butoxycarbonyl-N-[2-(3-indolyl)ethyl]hexylamine(compound 13; yield: 204 mg).

Step 4

6-(N-tert-Butoxycarbonyl)amino-(S)-2-amino-N-butoxycarbonyl-N-[2-(3-indolyl)ethyl]hexylamine

The compound 13 (195 mg, 0.78 mmol) was dissolved in a 10%piperidine/DMF solution, and stirred at room temperature for 20 minutes.This reaction solution was concentrated under reduced pressure, and theresultant residue was subjected to a column chromatography to obtain6-(N-tert-butoxycarbonyl)amino-(S)-2-amino-N-butoxycarbonyl-N-[2-(3-indolyl)ethyl]hexylamine(compound 14; yield: 129 mg).

Step 5

N′-α-9-Fluorenylmethoxycarbonyl-N-[5-(N′-tert-butoxycarbonyl)amino-(S)-1-[[N′-tert-butoxycarbonyl-N-[2-(3-indolyl)ethyl]aminomethyl]pentyl]-L-tyrosinamide

N-α-9-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine (133 mg, 0.29mmol) was dissolved in DMF (1 mL), combined with 1-hydroxybenzotriazole(43 mg, 0.32 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (WSC; 61 mg, 0.32 mmol) and stirred at room temperaturefor 10 minutes. This was cooled to 0° C., combined with the compound 14(125 mg, 0.26 mmol) dissolved in DMF (2 mL), and stirred further at roomtemperature overnight. The reaction solution was extracted with ethylacetate, washed with a saturated aqueous solution of sodium hydrogencarbonate, saturated brine and water. The organic layer was dried oversodium sulfate, made free of solids by filtration through a cotton plug,and washed with ethyl acetate. The filtrate and the wash were combinedand concentrated under reduced pressure, and the resultant residue wassubjected to a column chromatography to obtainN′-α-9-fluorenylmethoxycarbonyl-N-[5-(N-tert-butoxycarbonyl)amino-(S)-1-[N-tert-butoxycarbonyl-N-[2-(3-indolyl)ethyl]aminomethyl]pentyl]-L-tyrosinamide(compound 1; yield: 221 mg).

Step 6

N-[5-(N-tert-Butoxycarbonyl)amino-(S)-1-[N-tert-butoxycarbonyl-N-[2-(3-indolyl)ethyl]aminomethyl]pentyl]-(O-tert-butyl)-L-tyrosinamide

The compound 15 (210 mg, 0.23 mmol) was synthesized by the methodsimilar to that for the compound 14 to obtainN-[5-(N′-tert-butoxycarbonyl)amino-(S)-1-[N-tert-butoxycarbonyl-N-[2-(3-indolyl)ethyl]aminomethyl]pentyl]-(O-tert-butyl)-L-tyrosinamide(compound 16; yield: 80 mg).

Step 7

N-α-[6-(2,3-di-tert-Butoxycarbonyl)guanidinohexyl]-(O-tert-butyl)-L-tyrosinemethyl ester

O-tert-butyl-L-tyrosine methyl ester (200 mg, 0.69 mmol) and a crudeproduct of the compound 5 (320 mg, 0.89 mmol) were dissolved in methanol(3 mL), adjusted at pH4 with acetic acid, and then stirred at roomtemperature for 15 minutes. The reaction solution was cooled to 0° C.,combined with sodium cyanoborohydride (285 mg, 4.5 mmol), and thenstirred further at room temperature for 90 minutes. After completion ofthe reaction, the reaction solution was concentrated under reducedpressure, and the resultant residue was extracted with ethyl acetate,and the organic layer was washed with a saturated aqueous solution ofsodium hydrogen carbonate, saturated brine and water. The organic layerwas dried over sodium sulfate, made free of solids by filtration througha cotton plug, and washed with ethyl acetate. The filtrate and the washwere combined and concentrated under reduced pressure, and the resultantresidue was subjected to a column chromatography to obtainN-α-[6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl]-(O-tert-butyl)-L-tyrosinemethyl ester (compound 17; yield: 299 mg).

Step 8

N-α-[6-(2,3-di-tert-Butoxycarbonylguanidino)hexyl]-(O-tert-butyl)-L-tyrosinemethyl ester

The compound 17 (289 mg, 0.49 mmol) was dissolved in methylene chloride(5 mL), cooled to 0° C., combined with di-tert-butyl dicarbonate (426mg, 2.0 mmol) and triethylamine (0.4 mL), and stirred further at 40° C.overnight. After completion of the reaction, the reaction solution wascombined with ethyl acetate, and the organic layer was washed with a 6%aqueous solution of potassium hydrogen sulfate and a saturated aqueoussolution of sodium hydrogen carbonate. The organic layer was dried oversodium sulfate, made free of solids by filtration through a cotton plug,and washed with ethyl acetate. The filtrate and the wash were combinedand concentrated under reduced pressure, and the resultant residue wassubjected to a column chromatography to obtainN-α-[6-(2,3-di-tert-butoxycarbonylguanidino)hexyl]-(O-tert-butyl)-L-tyrosinemethyl ester (compound 18; yield: 241 mg).

Step 9

N-α-6-(2,3-di-tert-Butoxycarbonyl)guanidinohexyl-N-α-tert-butoxycarbonyl-(O-tert-butyl)-L-tyrosyl-N-[5-(N-tert-butoxycarbonyl)amino-(S)-1-[N-tert-butoxycarbonyl-N-[2-(3-indolyl)ethyl]aminomethyl]pentyl]-(O-tert-butyl)-L-tyrosinamide

The compound 18 (113 mg, 0.16 mmol) was dissolved in tetrahydrofuran (3mL), methanol (0.5 mL) and water (0.3 mL), combined with lithiumhydroxide monohydrate (22 mg, 0.52 mmol) and stirred at room temperaturefor 2 hours. After completion of the reaction, the reaction solution wascombined with ethyl acetate, and the organic layer was washed with a 6%aqueous solution of potassium hydrogen sulfate. The organic layer wasdried over sodium sulfate, made free of solids by filtration through acotton plug, washed with ethyl acetate, and the filtrate and the washwere combined and concentrated under reduced pressure. The resultantsyrup was dissolved in a 5% 1-hydroxybenzotriazole/DMF solution (3 mL),combined with the compound 16 (75 mg, 0.11 mmol),benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate(PyBOP; 95 mg, 0.18 mmol) and N,N-diisopropylethylamine (0.06 mL, 0.36mmol) and stirred at room temperature overnight. The reaction solutionwas extracted with ethyl acetate, washed with a saturated aqueoussolution of sodium hydrogen carbonate, saturated brine and water. Theorganic layer was dried over sodium sulfate, made free of solids byfiltration through a cotton plug, and washed with ethyl acetate. Thefiltrate and the wash were combined and concentrated under reducedpressure, and the resultant residue was subjected to a columnchromatography to obtainN-α-6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl-N-α-tert-butoxycarbonyl-(O-tert-butyl)-L-tyrosyl-N-[5-(N-tert-butoxycarbonyl)amino-(S)-1-[N-tert-butoxycarbonyl-N-[2-(3-indolyl)ethyl]aminomethyl]pentyl]-(O-tert-butyl)-L-tyrosinamide(compound 19; yield: 80 mg).

Step 10

N-α-6-Guanidinohexyl-L-tyrosyl-N-[5-amino-(S)-1-[[N-2-(3-indolyl)ethyl]aminomethyl]pentyl]-L-tyrosinamide

The compound 19 (80 mg, 0.06 mmol) was dissolved in a mixture oftrifluoroacetic acid (2.7 mL), ethanedithiol (0.15 mL) and water (0.15mL), and stirred at room temperature for 2 hours. After completion ofthe reaction, the reaction solution was poured into ether, and subjectedto a centrifuge to obtain a pellet. This was subjected to a highpressure column chromatography to obtainN-α-6-guanidinohexyl-L-tyrosyl-N-[5-amino-(S)-1-[[N-2-(3-indolyl)ethyl]aminomethyl]pentyl]-L-tyrosinamide(compound 20; yield: 33 mg).

FAB MS [M+H]⁺=742

EXAMPLE 4N-α-6-Guanidinohexyl-L-3-(2-naphthyl)-alanyl-N-[5-amino-(S)-1-[[N-[(S)-1-hydroxymethyl-2-(3-indolyl)]ethyl]aminomethyl]pentyl]-L-3-(2-naphthyl)-alaninamide

Step 1

6-(N-tert-Butoxycarbonyl)amino-(S)-2-(N-9-fluorenylmethoxycarbonyl)amino-N-[(S)-1-hydroxymethyl-2-(3-indolyl)ethyl]hexylamine

L-Tryptophanol (410 mg, 2.2 mmol) and a crude product of the compound 11(500 mg, 1.1 mmol) were dissolved in methanol (15 mL), adjusted at pH4with acetic acid, and then stirred at room temperature for 15 minutes.The reaction solution was cooled to 0° C., combined with sodiumcyanoborohydride (346 mg, 5.5 mmol) and stirred further at roomtemperature overnight. After completion of the reaction, the reactionsolution was concentrated under reduced pressure, and the resultantresidue was extracted with ethyl acetate, and the organic layer waswashed with a saturated aqueous solution of sodium hydrogen carbonate,saturated brine and water. The organic layer was dried over sodiumsulfate, made free of solids by filtration through a cotton plug, andwashed with ethyl acetate. The filtrate and the wash were combined andconcentrated under reduced pressure, and the resultant residue wassubjected to a column chromatography to obtain6-(N-tert-butoxycarbonyl)amino-(S)-2-(N-9-fluorenylmethoxycarbonyl)amino-N-[(S)-1-hydroxymethyl-2-(3-indolyl)ethyl]hexylamine(compound 21; yield: 431 mg).

Step 2

N-α-9-Fluorenylmethoxycarbonyl-N-[5-(N-tert-butoxycarbonyl)amino-(S)-1-[[N-[(S)-1-hydroxymethyl-2-(3-indolyl)]ethyl]aminomethyl]pentyl]-L-3-(2-naphthyl)-alaninamide

The compound 21 (350 mg, 0.56 mmol) was combined with a 10%piperidine/DMF solution (6 mL) and dissolved, stirred at roomtemperature for 20 minutes, and concentrated under reduced pressure. Theresultant syrup was dissolved in a 5% 1-hydroxybenzotriazole/DMFsolution (3 mL), combined withN-α-9-fluorenylmethoxycarbonyl-L-3-(2-naphthyl)-alanine (245 mg, 0.56mmol), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBOP; 320 mg, 0.62 mmol) andN,N-diisopropylethylamine (0.22 mL, 1.2 mmol) and stirred at roomtemperature overnight. The reaction solution was extracted with ethylacetate, washed with a saturated aqueous solution of sodium hydrogencarbonate, a saturated brine and water. The organic layer was dried oversodium sulfate, made free of solids by filtration through a cotton plug,and washed with ethyl acetate. The filtrate and the wash were combinedand concentrated under reduced pressure, and the resultant residue wassubjected to a column chromatography to obtainN-α-9-fluorenylmethoxycarbonyl-N-[5-(N-tert-butoxycarbonyl)amino-(S)-1-[[N-[(S)-1-hydroxymethyl-2-(3-indolyl)]ethyl]aminomethyl]pentyl]-L-3-(2-naphthyl)-alaninamide(compound 22; yield: 405 mg).

Step 3

N-α-9-Fluorenylmethoxycarbonyl-L-3-(2-naphthyl)-alanyl-N-[5-(N-tert-butoxycarbonyl)amino-(S)-1-[[N-[(S)-1-hydroxymethyl-2-(3-indolyl)]ethyl]aminomethyl]pentyl]-L-3-(2-naphthyl)-alaninamide

The compound 22 (350 mg, 0.42 mmol) was combined with a 10%piperidine/DMF solution (5 mL) and dissolved, stirred at roomtemperature for 20 minutes, and concentrated under reduced pressure. Theresultant syrup was dissolved in a 5% 1-hydroxybenzotriazole/DMFsolution (3 mL), combined withN-α-9-fluorenylmethoxycarbonyl-L-3-(2-naphthyl)-alanine (186 mg, 0.43mmol), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBOP; 243 mg, 0.47 mmol) andN,N-diisopropylethylamine (0.16 mL, 0.93 mmol) and stirred at roomtemperature for 2 hours. The reaction solution was extracted with ethylacetate, washed with a saturated aqueous solution of sodium hydrogencarbonate, a saturated brine and water. The organic layer was dried oversodium sulfate, made free of solids by filtration through a cotton plug,and washed with ethyl acetate. The filtrate and the wash were combinedand concentrated under reduced pressure, and the resultant residue wassubjected to a column chromatography to obtainN-α-9-fluorenylmethoxycarbonyl-L-3-(2-naphthyl)-alanyl-N-[5-(N-tert-butoxycarbonyl)amino-(S)-1-[[N-[(S)-1-hydroxymethyl-2-(3-indolyl)]ethyl]aminomethyl]pentyl]-L-3-(2-naphthyl)-alaninamide(compound 23; yield: 337 mg).

Step 4

L-3-(2-naphthyl)-alanyl-N-[5-(N-tert-butoxycarbonyl)amino-(S)-1-[[N-[(S)-1-hydroxymethyl-2-(3-indolyl)]ethyl]aminomethyl]pentyl]-L-3-(2-naphthyl)-alaninamide

The compound 23 (320 mg, 0.31 mmol) was reacted in accordance with themethod for synthesizing the compound 7 to obtainL-3-(2-naphthyl)-alanyl-N-[5-(N-tert-butoxycarbonyl)amino-(S)-1-[[N-[(S)-1-hydroxymethyl-2-(3-indolyl)]ethyl]aminomethyl]pentyl]-L-3-(2-naphthyl)-alaninamide(compound 24; yield: 169 mg).

Step 5

N-α-6-(2,3-di-tert-Butoxycarbonyl)guanidinohexyl-L-3-(2-naphthyl)-alanyl-N-[5-(N′-tert-butoxycarbonyl)amino-(S)-1-[[N-[(S)-1-hydroxymethyl-2-(3-indolyl)]ethyl]aminomethyl]pentyl]-L-3-(2-naphthyl)-alaninamide

The compound 24 (92 mg, 0.11 mmol) and a crude product of the compound 5(68 mg, 0.19 mmol) were reacted in accordance with the method forsynthesizing the compound 6 to obtainN-α-6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl-L-3-(2-naphthyl)-alanyl-N-[5-(N′-tert-butoxycarbonyl)amino-(S)-1-[[N-[(S)-1-hydroxymethyl-2-(3-indolyl)]ethyl]aminomethyl]pentyl]-L-3-(2-naphthyl)-alaninamide(compound 25; yield: 64 mg).

Step 6

N-α-6-Guanidinohexyl-L-3-(2-naphthyl)-alanyl-N-[5-amino-(S)-1-[[N′-[(S)-1-hydroxymethyl-2-(3-indolyl)]ethyl]aminomethyl]pentyl]-L-3-(2-naphthyl)-alaninamide

The compound 25 (64 mg, 0.06 mmol) was reacted in accordance with themethod for synthesizing the compound 20 to obtainN-α-6-guanidinohexyl-L-3-(2-naphthyl)-alanyl-N-[5-amino-(S)-1-[[N′-[(S)-1-hydroxymethyl-2-(3-indolyl)]ethyl]aminomethyl]pentyl]-L-3-(2-naphthyl)-alaninamide(compound 26; yield: 14 mg).

FAB MS [M+H]⁺=840

EXAMPLE 5N-α-6-Guanidinohexyl-L-3-(1-naphthyl)-alanyl-L-tyrosyl-L-lysyl-L-tryptophanamide(SEQ. ID. NO 3)

Step 1

N-ε-tert-butoxycarbonyl-L-lysyl-L-tryptophanamide

N-α-9-fluorenylmethoxycarbonyl-N-ε-tert-butoxycarbonyl-lysine (5.9 g,12.6 mmol) and L-tryptophanamide hydrochloride (3.0 g, 12.5 mmol) arereacted in accordance with the method for synthesizing the compound 1 toobtain N-ε-tert-butoxycarbonyl-L-lysyl-L-tryptophanamide (compound 27;yield: 5.3 g).

Step 2

O-tert-butyl-L-Tyrosyl-N-ε-tert-butoxycarbonyl-L-lysyl-L-tryptophanamide

N-α-9-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine (5.7 g, 12.3mmol) and the compound 27 (5.3 g, 12.3 mmol) were reacted in accordancewith the method for synthesizing the compound 1 to obtainO-tert-butyl-L-tyrosyl-N-ε-tert-butoxycarbonyl-L-lysyl-L-tryptophanamide(compound 28; yield: 7.7 g).

Step 3

N-α-9-Fluorenylmethoxycarbonyl-L-3-(1-naphthyl)-alanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide

N-α-9-fluorenylmethoxycarbonyl-L-3-(1-naphthyl)-alanine (168 mg, 0.38mmol) was dissolved in DMF (2 mL), combined with 1-hydroxybenzotriazole(57 mg, 0.42 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (WSC; 81 mg, 0.42 mmol) and stirred at room temperaturefor 10 minutes. This was cooled to 0° C., combined with the compound 28(250 mg, 0.38 mmol) and stirred further at room temperature overnight.The reaction solution was extracted with ethyl acetate, washed with asaturated aqueous solution of sodium hydrogen carbonate, a saturatedbrine and water. The organic layer was dried over sodium sulfate, madefree of solids by filtration through a cotton plug, and washed withethyl acetate. The filtrate and the wash were combined and concentratedunder reduced pressure. The resultant residue was combined withpetroleum ether to form a crystal, which was then recovered byfiltration to obtainN-α-9-fluorenylmethoxycarbonyl-L-3-(1-naphthyl)-alanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 29; yield: 359 mg).

Step 4

L-3-(1-Naphthyl)-alanyl-(O-tert-butyl)-L-tyrosyl-N-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide

The compound 29 (350 mg, 0.33 mmol) was reacted in accordance with themethod for synthesizing the compound 14 to obtainL-3-(1-naphthyl)-alanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 30; yield: 269 mg).

Step 5

N-α-[6-(2,3-di-tert-Butoxycarbonylguanidino)hexyl]-L-3-(1-naphthyl)-alanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(SEQ. ID. NO 4)

The compound 30 (100 mg, 0.12 mmol) and a crude product of the compound5 (85 mg, 0.24 mmol) were reacted in accordance with the method forsynthesizing the compound 6 to obtainN-α-[6-(2,3-di-tert-butoxycarbonylguanidino)hexyl]-L-3-(1-naphthyl)-alanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 31; yield: 51 mg).

Step 6

N-α-6-Guanidinohexyl-L-3-(1-naphthyl)-alanyl-L-tyrosyl-L-lysyl-L-tryptophanamide(SEQ. ID. NO 3)

The compound 31 (51 mg, 0.04 mmol) was reacted in accordance with themethod for synthesizing the compound 20 to obtainN-α-6-guanidinohexyl-L-3-(1-naphthyl)-alanyl-L-tyrosyl-L-lysyl-L-tryptophanamide(compound 32; yield: 27 mg).

FAB MS [M+H]⁺=833

EXAMPLE 6N-α-6-Guanidinohexyl-L-3-(2-naphthyl)-alanyl-L-tyrosyl-L-lysyl-L-tryptophanamide(SEQ. ID. NO 3)

Step 1

N-α-9-Fluorenylmethoxycarbonyl-L-3-(2-naphthyl)-alanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide

N-α-9-Fluorenylmethoxycarbonyl-L-3-(2-naphthyl)-alanine (168 mg, 0.38mmol) was reacted in accordance with the method for synthesizing thecompound 29 to obtainN-α-9-fluorenylmethoxycarbonyl-L-3-(2-naphthyl)-alanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 33; yield: 355 mg).

Step 2

L-3-(2-Naphthyl)-alanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide

The compound 33 (350 mg, 0.33 mmol) was reacted in accordance with themethod for synthesizing the compound 14 to obtainL-3-(2-naphthyl)-alanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 34; yield: 276 mg).

Step 3

N-α-[6-(2,3-di-tert-butoxycarbonylguanidino)hexyl]-L-3-(2-naphthyl)-alanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide

The compound 34 (100 mg, 0.12 mmol) was reacted in accordance with themethod for synthesizing the compound 6 to obtainN-α-[6-(2,3-di-tert-butoxycarbonylguanidino)hexyl]-L-3-(2-naphthyl)-alanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 35; yield: 44 mg).

Step 4

N-α-6-Guanidinohexyl-L-3-(2-naphthyl)-alanyl-L-tyrosyl-L-lysyl-L-tryptophanamide(SEQ. ID. NO 3)

The compound 35 (44 mg, 0.04 mmol) was reacted in accordance with themethod for synthesizing the compound 20 to obtainN-α-6-guanidinohexyl-L-3-(2-naphthyl)-alanyl-L-tyrosyl-L-lysyl-L-tryptophanamide(compound 36; yield: 25 mg).

FAB MS [M+H]⁺=833

EXAMPLE 7N-α-6-Guanidinohexyl-L-4,4′-biphenylalanyl-L-tyrosyl-L-lysyl-L-tryptophanamide(SEQ. ID. NO 3)

Step 1

N-α-9-Fluorenylmethoxycarbonyl-L-4,4′-biphenylalanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide

N-α-9-fluorenylmethoxycarbonyl-L-4,4′-biphenylalanine (178 mg, 0.38mmol) was reacted in accordance with the method for synthesizing thecompound 29 to obtainN-α-9-fluorenylmethoxycarbonyl-L-4,4′-biphenylalanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 37; yield: 391 mg).

Step 2

L-4,4′-Biphenylalanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide

The compound 37 (380 mg, 0.35 mmol) was reacted in accordance with themethod for synthesizing the compound 14 to obtainL-4,4′-biphenylalanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 38; yield: 296 mg).

Step 3

N-α-[6-(2,3-di-tert-Butoxycarbonylguanidino)hexyl]-L-4,4′-biphenylalanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(SEQ. ID. NO 4)

The compound 38 (150 mg, 0.17 mmol) and a crude product of the compound5 (102 mg, 0.29 mmol) were reacted in accordance with the method forsynthesizing the compound 6 to obtainN-α-[6-(2,3-di-tert-butoxycarbonylguanidino)hexyl]-L-4,4′-biphenylalanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 39; yield: 120 mg).

Step 4

N-α-6-Guanidinohexyl-L-4,4′-biphenylalanyl-L-tyrosyl-L-lysyl-L-tryptophanamide(SEQ. ID. NO 4)

The compound 39 (120 mg, 0.10 mmol) was reacted in accordance with themethod for synthesizing the compound 20 to obtainN-α-6-guanidinohexyl-L-4,4′-biphenylalanyl-L-tyrosyl-L-lysyl-L-tryptophanamide(compound 40; yield: 78 mg).

FAB MS [M+H]⁺=859

EXAMPLE 8N-α-6-Guanidinohexyl-4-fluoro-L-phenylalanyl-L-tyrosyl-L-lysyl-L-tryptophanamide(SEQ. ID. NO 5)

Step 1

N-α-9-Fluorenylmethoxycarbonyl-4-fluoro-L-phenylalanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide

N-α-9-fluorenylmethoxycarbonyl-4-fluoro-L-phenylalanine (156 mg, 0.38mmol) was reacted in accordance with the method for synthesizing thecompound 29 to obtainN-α-9-fluorenylmethoxycarbonyl-4-fluoro-L-phenylalanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 41; yield: 379 mg).

Step 2

4-Fluoro-L-phenylalanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide

The compound 41 (370 mg, 0.37 mmol) was reacted in accordance with themethod for synthesizing the compound 14 to obtain4-fluoro-L-phenylalanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 42; yield: 280 mg).

Step 3

N-α-[6-(2,3-di-tert-Butoxycarbonylguanidino)hexyl]-4-fluoro-L-phenylalanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(SEQ. ID. NO 6)

The compound 42 (150 mg, 0.18 mmol) and a crude product of the compound5 (102 mg, 0.29 mmol) were reacted in accordance with the method forsynthesizing the compound 6 to obtainN-α-[6-(2,3-di-tert-butoxycarbonylguanidino)hexyl]-4-fluoro-L-phenylalanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 43; yield: 122 mg).

Step 4

N-α-6-Guanidinohexyl-4-fluoro-L-phenylalanyl-L-tyrosyl-L-lysyl-L-tryptophanamide(SEQ. ID. NO 5)

The compound 43 (122 mg, 0.11 mmol) was reacted in accordance with themethod for synthesizing the compound 20 to obtainN-α-6-guanidinohexyl-4-fluoro-L-phenylalanyl-L-tyrosyl-L-lysyl-L-tryptophanamide(compound 44; yield: 75 mg).

FAB MS [M+H]⁺=801

EXAMPLE 9N-α-6-guanidinohexyl-4-amino-L-phenylalanyl-L-tyrosyl-L-lysyl-L-tryptophanamide(SEQ. ID. NO 5)

Step 1

N-α-9-Fluorenylmethoxycarbonyl-4-amino-N-tert-butoxycarbonyl-L-phenylalanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide

N-α-9-fluorenylmethoxycarbonyl-4-amino-N-tert-butoxycarbonyl-L-phenylalanine(197 mg, 0.39 mmol) was reacted in accordance with the method forsynthesizing the compound 29 to obtainN-α-9-fluorenylmethoxycarbonyl-4-amino-N-tert-butoxycarbonyl-L-phenylalanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 45; yield: 416 mg).

Step 2

4-Amino-N-tert-butoxycarbonyl-L-phenylalanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide

The compound 45 (410 mg, 0.36 mmol) was reacted in accordance with themethod for synthesizing the compound 14 to obtain4-amino-N-tert-butoxycarbonyl-L-phenylalanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 46; yield: 305 mg).

Step 3

N-α-[6-(2,3-di-tert-Butoxycarbonylguanidino)hexyl]-4-amino-N-tert-butoxycarbonyl-L-phenylalanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(SEQ. ID. NO 6)

The compound 46 (166 mg, 0.18 mmol) and a crude product of the compound5 (98 mg, 0.27 mmol) were reacted in accordance with the method forsynthesizing the compound 6 to obtainN-α-[6-(2,3-di-tert-butoxycarbonylguanidino)hexyl]-4-amino-N-tert-butoxycarbonyl-L-phenylalanyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 47; yield: 106 mg).

Step 4

N-α-6-Guanidinohexyl-4-amino-L-phenylalanyl-L-tyrosyl-L-lysyl-L-tryptophanamide(SEQ. ID. NO 5)

The compound 47 (106 mg, 0.08 mmol) was reacted in accordance with themethod for synthesizing the compound 20 to obtainN-α-6-guanidinohexyl-4-amino-L-phenylalanyl-L-tyrosyl-L-lysyl-L-tryptophanamide(compound 48; yield: 55 mg).

FAB MS [M+H]⁺=798

EXAMPLE 10N-α-6-Guanidinohexyl-L-2-indanyl-glycyl-L-tyrosyl-L-lysyl-L-tryptophanamide(SEQ. ID. NO 7)

Step 1

N-α-9-fluorenylmethoxycarbonyl-L-2-indanyl-glycyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide

N-α-9-fluorenylmethoxycarbonyl-L-2-indanyl-glycine (159 mg, 0.38 mmol)was reacted in accordance with the method for synthesizing the compound29 to obtainN-α-9-fluorenylmethoxycarbonyl-L-2-indanyl-glycyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 49; yield: 405 mg).

Step 2

L-2-Indanyl-glycyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide

The compound 49 (400 mg, 0.38 mmol) was reacted in accordance with themethod for synthesizing the compound 14 to obtainL-2-indanyl-glycyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 50; yield: 281 mg).

Step 3

N-α-[6-(2,3-di-tert-Butoxycarbonylguanidino)hexyl]-L-2-indanyl-glycyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(SEQ. ID. NO 8)

The compound 50 (150 mg, 0.18 mmol) and a crude product of the compound5 (98 mg, 0.27 mmol) were reacted in accordance with the method forsynthesizing the compound 6 to obtainN-α-[6-(2,3-di-tert-butoxycarbonylguanidino)hexyl]-L-2-indanyl-glycyl-(O-tert-butyl)-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 51; yield: 93 mg).

Step 4

N-α-6-Guanidinohexyl-L-2-indanyl-glycyl-L-tyrosyl-L-lysylL-tryptophanamide (SEQ. ID. NO 7)

The compound 51 (93 mg, 0.08 mmol) was reacted in accordance with themethod for synthesizing the compound 20 to obtainN-α-6-guanidinohexyl-L-2-indanyl-glycyl-L-tyrosyl-L-lysyl-L-tryptophanamide(compound 52; yield: 57 mg).

FAB MS [M+H]⁺=809

EXAMPLE 11N-α-6-guanidinohexyl-L-tyrosyl-L-tyrosyl-L-lysyl-L-tryptophanol (SEQ.ID. NO 9)

Step 1

N-9-Fuorenylmethoxycarbonyl-N-ε-tert-butoxycarbonyl-lysine benzyl ester

N-9-Fluorenylmethoxycarbonyl-N-ε-tert-butoxycarbonyl-lysine (6.0 g, 12.8mmol) and benzyl alcohol (1.6 mL, 15.5 mmol) was dissolved in methylenechloride (50 mL), cooled to 0° C., combined with dimethylaminopyridine(142 mg, 1.2 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (WSC; 2.7 g, 14.1 mmol), stirred at 0° C. for 2 hours, andfurther stirred at room temperature overnight. The reaction solution wasextracted with chloroform, washed with a saturated aqueous solution ofsodium hydrogen carbonate, saturated brine and water. The organic layerwas dried over sodium sulfate, made free of solids by filtration througha cotton plug and washed with chloroform. The filtrate and the wash werecombined and concentrated under reduced pressure, and the resultantresidue was subjected to a column chromatography to obtainN-9-fluorenylmethoxycarbonyl-N-ε-tert-butoxycarbonyl-lysine benzyl ester(compound 53; yield: 7.1 g).

Step 2

N-ε-tert-Butoxycarbonyl-lysine benzyl ester

The compound 53 was reacted in accordance with the method forsynthesizing the compound 14 to obtain N-ε-tert-butoxycarbonyl-lysinebenzyl ester (compound 54; yield: 4.1 g).

Step 3

N-α-9-Fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosyl-N-ε-(tert-butoxycarbonyl)-L-lysinebenzyl ester

N-α-9-Fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine (5.6 g, 12.2mmol) was dissolved in DMF (65 mL), combined with 1-hydroxybenzotriazole(1.8 g, 13.3 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (WSC; 2.6 g, 13.4 mmol) and stirred at room temperaturefor 10 minutes. This was cooled to 0° C., combined with the compound 54(4.1 g, 12.2 mmol) and stirred further at room temperature overnight.The reaction solution was extracted with ethyl acetate, washed with asaturated aqueous solution of sodium hydrogen carbonate, saturated brineand water. The organic layer was dried over sodium sulfate, made free ofsolids by filtration through a cotton plug, washed with ethyl acetate,and the filtrate and the wash were combined and concentrated underreduced pressure. The resultant reaction product was evaporatedsufficiently into dryness under reduced pressure to obtainN-α-9-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosyl-N-ε-tert-butoxycarbonyl-L-lysinebenzyl ester (compound 55; yield: 9.4 g).

Step 4

O-tert-butyl-L-Tyrosyl-O-tert-butyl-L-tyrosyl-N-ε-tert-butoxycarbonyl-L-lysinebenzyl ester

The compound 55 (9.4 g, 12.1 mmol) was dissolved in DMF (80 mL) andcooled to 0° C. with stirring while cooling on ice. This was combinedwith piperidine (6.0 mL, 61 mmol), stirred further for 25 minutes, andthen the reaction solution was poured into water, and extracted withethyl acetate. The organic layer was washed with a 6% aqueous solutionof potassium hydrogen sulfate, a saturated aqueous solution of sodiumhydrogen carbonate, saturated brine and water. The organic layer wasdried over sodium sulfate, made free of solids by filtration through acotton plug, and washed with ethyl acetate. The filtrate and the washwere combined and concentrated under reduced pressure. The resultantresidue was dissolved in DMF (20 mL), poured into a solution preparedpreviously by dissolvingN-α-9-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine (5.6 g, 12.2mmol) in DMF (65 mL), adding 1-hydroxybenzotriazole (1.8 g, 13.3 mmol)and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC;2.6 g, 13.4 mmol), stirring at room temperature for 10 minutes and thencooling to 0° C., and then stirred further at room temperatureovernight. The reaction solution was extracted with ethyl acetate,washed with a saturated aqueous solution of sodium hydrogen carbonate,saturated brine and water. The organic layer was dried over sodiumsulfate, made free of solids by filtration through a cotton plug, andwashed with ethyl acetate. The filtrate and the wash were combined andconcentrated under reduced pressure. The resultant syrup was combinedwith a 10% piperidine/DMF solution (120 mL) and dissolved, and thenstirred at room temperature for 20 minutes. The reaction solution wasconcentrated under reduced pressure, and the resultant residue wassubjected to a column chromatography to obtainO-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-ε-tert-butoxycarbonyl-L-lysinebenzyl ester (compound 56; yield: 8.6 g).

Step 5

N-α-[6-(2,3-di-tert-Butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-ε-tert-butoxycarbonyl-L-lysinebenzyl ester (SEQ. ID. NO 10)

The compound 56 (4 g, 5.2 mmol) and a crude product of the compound 5(2.2 g, 6.1 mmol) were reacted in accordance with the method forsynthesizing the compound 6 to obtainN-α-[6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-(N-ε-tert-butoxycarbonyl)-L-lysinebenzyl ester (compound 57; yield: 2.2 g).

Step 6

N-α-[6-(2,3-di-tert-Butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-ε-tert-butoxycarbonyl-L-lysine(SEQ. ID. NO 10)

The compound 57 (2.2 g, 1.97 mmol) was dissolved in methanol (100 mL),combined with acetic acid (10 mL) and 10% Pd-C (500 mg), and stirred atroom temperature for 5 hours. The reaction solution was filtered throughCelite to remove solids, and washed with methanol. The filtrate and thewash were combined and concentrated under reduced pressure, and theresultant residue was combined with ethyl acetate and extracted, and theorganic layer was washed with a saturated aqueous solution of sodiumhydrogen carbonate, saturated brine and water. The organic layer wasdried over sodium sulfate, made free of solids by filtration through acotton plug, and washed with ethyl acetate. The filtrate and the washwere combined and concentrated under reduced pressure to obtainN-α-[6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-(N-ε-tert-butoxycarbonyl)-L-lysine(compound 58; yield: 1.9 g).

Step 7

N-α-[6-(2,3-di-tert-Butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-ε-tert-butoxycarbonyl-L-lysyl-L-tryptophanol(SEQ. ID. NO 10)

L-Tryptophanol (37 mg, 0.19 mmol) and the compound 58 (100 mg, 0.10mmol) were dissolved in DMF (2 mL), combined with 1-hydroxybenzotriazole(15 mg, 0.11 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (WSC; 21 mg, 0.11 mmol) and stirred at room temperatureovernight. The reaction solution was extracted with ethyl acetate,washed with a saturated aqueous solution of sodium hydrogen carbonate,saturated brine and water. The organic layer was dried over sodiumsulfate, made free of solids by filtration through a cotton plug, washedwith ethyl acetate, and the filtrate and the wash were combined andconcentrated under reduced pressure. The resultant residue was subjectedto a column chromatography to obtainN-α-[6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-ε-tert-butoxycarbonyl-L-lysyl-L-tryptophanol(compound 59; yield: 106 mg).

Step 8

N-α-6-Guanidinohexyl-L-tyrosyl-L-tyrosyl-L-lysyl-L tryptophanol (SEQ.ID. NO 9)

The compound 59 (106 mg, 0.09 mmol) was reacted in accordance with themethod for synthesizing the compound 20 to obtainN-α-6-guanidinohexyl-L-tyrosyl-L-tyrosyl-L-lysyl-L-tryptophanol(compound 60; yield: 45 mg).

FAB MS [M+H]⁺=786

EXAMPLE 12N-α-6-Guanidinohexyl-L-tyrosyl-L-tyrosyl-L-lysyl-L-phenylalaninol (SEQ.ID. NO 11)

Step 1

N-α-[6-(2,3-di-tert-Butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-Ltyrosyl-N-ε-tert-butoxycarbonyl-L-lysyl-L-phenylalaninol (SEQ. ID. NO12)

L-phenylalaninol (30 mg, 0.20 mmol) and the compound 58 (100 mg, 0.10mmol) was reacted in accordance with the method for synthesizing thecompound 59 to obtainN-α-[6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-ε-tert-butoxycarbonyl-L-lysyl-L-phenylalaninol(compound 61; yield: 111 mg).

Step 2

N-α-6-Guanidinohexyl-L-tyrosyl-L-tyrosyl-L-lysyl-L-phenylalaninol (SEQ.ID. NO 11)

The compound 61 (111 mg, 0.10 mmol) was reacted in accordance with themethod for synthesizing the compound 20 to obtainN-α-6-guanidinohexyl-L-tyrosyl-L-tyrosyl-L-lysyl-L-phenylalaninol(compound 62; yield: 57 mg).

FAB MS [M+H]⁺=747

EXAMPLE 13N-α-6-Guanidinohexyl-L-tyrosyl-L-tyrosyl-N-benzyl-N-(2-hydroxyethyl)-L-lysinamide

Step 1

N-α-[6-(2,3-di-tert-Butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-benzyl-N-(2-hydroxyethyl)-N-ε-tert-butoxycarbonyl-L-lysinamide

N-Benzylethanolamine (35 mg, 0.23 mmol) and the compound 58 (120 mg,0.12 mmol) were reacted in accordance with the method for synthesizingthe compound 59 to obtainN-α-[6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-benzyl-N-(2-hydroxyethyl)-N-ε-tert-butoxycarbonyl-L-lysinamide(compound 63; yield: 81 mg).

Step 2

N-α-6-Guanidinohexyl-L-tyrosyl-L-tyrosyl-N-benzyl-N-(2-hydroxyethyl)-L-lysinamide

The compound 63 (81 mg, 0.07 mmol) was reacted in accordance with themethod for synthesizing the compound 20 to obtainN-α-6-guanidinohexyl-L-tyrosyl-L-tyrosyl-N-benzyl-N-(2-hydroxyethyl)-N-ε-tert-butoxycarbonyl-L-lysinamide(compound 64; yield: 9.0 mg).

FAB MS [M+H]⁺=747

EXAMPLE 14N-α-6-guanidinohexyl-L-tyrosyl-L-tyrosyl-N-(1-naphthalenemethyl)-L-lysinamide

Step 1

N-α-[6-(2,3-di-tert-Butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-(1-naphthalenemethyl)-N-ε-tert-butoxycarbonyl-L-lysinamide

1-Naphthalene methylamine (31 mg, 0.20 mmol) and the compound 58 (120mg, 0.12 mmol) were reacted in accordance with the method forsynthesizing the compound 59 to obtainN-α-[6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-(N-1-naphthalenemethyl)-N-ε-tert-butoxycarbonyl-L-lysinamide(compound 65; yield: 101 mg).

Step 2

N-α-6-Guanidinohexyl-L-tyrosyl-L-tyrosyl-N-(1-naphthalenemethyl)-L-lysinamide

The compound 20 (101 mg, 0.09 mmol) was reacted in accordance with themethod for synthesizing the compound 60 to obtainN-α-6-guanidinohexyl-L-tyrosyl-L-tyrosyl-(N-1-naphthalenemethyl)-L-lysinamide(compound 66; yield: 63 mg).

FAB MS [M+H]⁺=753

EXAMPLE 15N-α-6-Guanidinohexyl-D-tyrosyl-L-tyrosyl-L-lysyl-L-tryptophanamide (SEQ.ID. NO 9)

Step 1

O-tert-Butyl-D-tyrosyL-O-tert-butyl-L-tyrosyl-N-ε-tert-butoxycarbonyl-L-lysyl-L-tryptophanamide(SEQ. ID. NO 9)

N-α-9-Fluorenylmethoxycarbonyl-O-tert-butyl-D-tyrosine (206 mg, 0.45mmol) and the compound 28 (300 mg, 0.46 mmol) were reacted in accordancewith the method for synthesizing the compound 1 to obtain(O-tert-butyl)-D-tyrosyl-(O-tert-butyl)-L-tyrosyl-(N-ε-tert-butoxycarbonyl)-L-lysyl-L-tryptophanamide(compound 67; yield: 362 mg).

Step 2

N-α-[6-(2,3-di-tert-Butoxycarbonyl)guanidinohexyl]-(O-tert-butyl)-D-tyrosyl-(O-tert-butyl)-L-tyrosyl-N-ε-tert-butoxycarbonyl-L-lysyl-L-tryptophanamide(SEQ. ID. NO 10)

A crude product of the compound 5 (83.3 mg) and the compound 67 (150 mg,0.17 mmol) were reacted in accordance with the method for synthesizingthe compound 6 to obtainN-α-[6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl]-O-tert-butyl-D-tyrosyl-O-tert-butyl-L-tyrosyl-N-ε-tert-butoxycarbonyl-L-lysyl-L-tryptophanamide(compound 68; yield: 124 mg).

Step 3

N-α-6-guanidinohexyl-D-tyrosyl-L-tyrosyl-L-lysyl-L-tryptophanamide (SEQ.ID. NO 9)

The compound 68 (124 mg, 0.10 mmol) was reacted in accordance with themethod for synthesizing the compound 20 to obtainN-α-6-guanidinohexyl-D-tyrosyl-L-tyrosyl-L-lysyl-L-tryptophanamide(compound 69; yield: 51.1 mg).

FAB MS [M+H]⁺=799

EXAMPLE 16N-α-6-Guanidinohexyl-N-methyl-L-tyrosyl-L-tyrosyl-L-lysyl-L-tryptophanamide(SEQ. ID. NO 9)

Step 1

N-α-[6-(2,3-di-tert-Butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosinebenzyl ester

A crude product of the compound 5 (2.4 g) and O-tert-butyl-L-tyrosinebenzyl ester (1.78 g, 5.4 mmol) were reacted in accordance with themethod for synthesizing the compound 6 to obtainN-α-[6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosinebenzyl ester (compound 70; yield: 1.32 g).

Step 2

N-α-[6-(2,3-di-tert-Butoxycarbonyl)guanidinohexyl]-N-methyl-O-tert-butyl-L-tyrosinebenzyl ester

The compound 70 (260 mg, 0.39 mmol) was dissolved in a mixture ofmethanol (2.7 mL) and formaldehyde solution (2.7 mL), adjusted at pH4with acetic acid, and then combined with sodium cyanoborohydride (54.0mg, 0.86 mmol) and stirred at room temperature for 30 minutes. Aftercompletion of the reaction, the reaction solution was concentrated underreduced pressure, and the resultant residue was extracted with ethylacetate, and the organic layer was washed with a saturated aqueoussolution of sodium hydrogen carbonate, saturated brine and water. Theorganic layer was dried over sodium sulfate, made free of solids byfiltration through a cotton plug, and washed with ethyl acetate. Thefiltrate and the wash were combined and concentrated under reducedpressure, and the resultant residue was subjected to a columnchromatography to obtainN-α-[6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl]-N-methyl-O-tert-butyl-L-tyrosinebenzyl ester (compound 71; yield: 197 mg).

Step 3

N-α-[6-(2,3-di-tert-Butoxycarbonylguanidino)hexyl]-N-methyl-O-tert-butyl-L-tyrosine

The compound 71 (197 mg, 0.29 mmol) was reacted in accordance with themethod for synthesizing compound 58 to obtainN-α-[6-(2,3-di-tert-butoxycarbonylguanidino)hexyl]-N-methyl-(O-tert-butyl)-L-tyrosine(compound 72; yield: 164 mg).

Step 4

N-α-[6-(2,3-di-tert-Butoxycarbonylguanidino)hexyl]-N-methyl-O-tert-butyl-L-tyrosyl-O-tertbutyl-L-tyrosyl-N-ε-tert-butoxycarbonyl-L-lysyl-L-tryptophanamide (SEQ.ID. NO 10)

The compound 72 (88.7 mg, 0.15 mmol) and the compound 28 (97.4 mg, 0.15mmol) were dissolved in DMF (3 mL), combined with WSC (31.6 mg, 0.16mmol) and 1-hydroxybenzotriazole (22.2 mg, 0.16 mmol) and stirredovernight. The reaction solution was extracted with ethyl acetate,washed with a saturated aqueous solution of sodium hydrogen carbonate,saturated brine and water. The organic layer was dried over sodiumsulfate, made free of solids by filtration through a cotton plug, andwashed with ethyl acetate. The filtrate and the wash were combined andconcentrated under reduced pressure, and the resultant residue wassubjected to a column chromatography to obtainN-α-[6-(2,3-di-tert-butoxycarbonylguanidino)hexyl]-N-methyl-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-ε-tert-butoxycarbonyl-L-lysyl-L-tryptophanamide(compound 73; yield: 115 mg).

Step 5

N-α-6-Guanidinohexyl-N-methyl-L-tyrosyl-L-tyrosyl-L-lysyl-L-tryptophanamide(SEQ. ID. NO 9)

The compound 73 (115 mg, 0.09 mmol) was reacted in accordance with themethod for synthesizing the compound 20 to obtainN-α-6-guanidinohexyl-N-methyl-L-tyrosyl-L-tyrosyl-L-lysyl-L-tryptophanamide(compound 74; yield: 65.2 mg).

FAB MS [M+H]⁺=813

EXAMPLE 17N-α-6-Guanidinohexyl-L-tyrosyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-lysinamide

Step 1

N-α-[6-(2,3-di-tert-Butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ε-tert-butoxycarbonyl-L-lysinamide

R-(+)-1-(2-Naphthyl)ethylamine (33.4 mg, 0.20 mmol) and the compound 58(100 mg, 0.10 mmol) were reacted in accordance with the method forsynthesizing the compound 59 to obtainN-α-[6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ε-tert-butoxycarbonyl-L-lysinamide(compound 75; yield: 78.3 mg).

Step 2

N-α-6-Guanidinohexyl-L-tyrosyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-lysinamide

The compound 75 (78.3 mg, 0.07 mmol) was reacted in accordance with themethod for synthesizing the compound 20 to obtainN-α-6-guanidinohexyl-L-tyrosyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-lysinamide(compound 76; yield: 50 mg).

FAB MS [M+H]⁺=767

EXAMPLE 18N-α-[(S)-2-N′-[N″-6-Guanidinohexyl-L-tyrosyl]amino-3-(4-hydroxy)phenyl]propyl-L-lysyl-L-tryptophanamide

Step 1

N-α-[3-(4-O-tert-Butyl)phenyl-(S)-2-N-(9-fluorenylmethoxycarbonyl)amino]-propyl-N-ε-tert-butoxycarbonyl-L-lysyl-L-tryptophanamide

N-α-9-Fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosinol (929 mg, 2.09mmol) was dissolved in methylene chloride (20 mL), combined withDess-Martin reagent (3.1 g, 7.3 mmol) and stirred for 10 minutes. Aftercompletion of the solution, the reaction solution was combined with asaturated aqueous solution of sodium hydrogen carbonate and an aqueoussolution of sodium thiosulfate, stirred for 10 minutes, and extractedwith ether. The organic layer was dried over sodium sulfate, made freeof solids by filtration through a cotton plug, and then washed withether. The filtrate and the wash were combined and concentrated underreduced pressure to obtain a crude product ofN-α-9-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosinal. This crudeproduct and the compound 27 (600 mg, 1.39 mmol) were dissolved inmethanol (5 mL), adjusted at pH4 with acetic acid, and then stirred atroom temperature for 15 minutes. The reaction solution was cooled to 0°C., combined with sodium cyanoborohydride (393 mg, 6.25 mmol) andstirred at room temperature for 15 minutes. After completion of thereaction, the reaction solution was concentrated under reduced pressure,and the resultant residue was extracted with ethyl acetate, and theorganic layer was washed with a saturated aqueous solution of sodiumhydrogen carbonate, saturated brine and water. The organic layer wasdried over sodium sulfate, made free of solids by filtration through acotton plug, and washed with ethyl acetate. The filtrate and the washwere combined and concentrated under reduced pressure, and the resultantresidue was subjected to a column chromatography to obtainN-α-[3-(4-O-tert-butyl)phenyl-(S)-2-N-(9-fluorenylmethoxycarbonyl)amino]-propyl-N-ε-tert-butoxycarbonyl-L-lysyl-L-tryptophanamide(compound 77; yield: 872.5 mg).

Step 2

N-α-[(S)-2-Amino-3-(4-O-tert-butyl)phenyl]propyl-N-ε-tert-butoxycarbonyl-L-lysyl-L-tryptophanamide

The compound 77 (400 mg, 46.6 mmol) was reacted in accordance with themethod for synthesizing the compound 14 to obtainN-α-[(S)-2-amino-3-(4-O-tert-butyl)phenyl]propyl-N-ε-tert-butoxycarbonyl-L-lysyl-L-tryptophanamide(compound 78; yield: 294 mg).

Step 3

N-α-[6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosine

The compound 70 (600 mg, 0.90 mmol) was reacted in accordance with themethod for synthesizing the compound 58 to obtainN-α-[6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosine(compound 79; yield: 483 mg).

Step 4

N-α-[(S)-2-N′-[N-α-{6-(2,3-di-tert-Butoxycarbonyl)guanidinohexyl}-O-tert-butyl-L-tyrosyl]amino-3-(4-O-tert-butyl)phenyl]propyl-N-ε-tert-butoxycarbonyl-L-lysyl-L-tryptophanamide

The compound 78 (66.0 mg, 0.10 mmol) and the compound 79 (60.0 mg, 0.10mmol) were reacted in accordance with the method for synthesizing thecompound 73 to obtain N-α-[(S)-2-N′-[N-α-{6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl}-O-tert-butyl-L-tyrosyl]amino-3-(4-O-tert-butyl)phenyl]propyl-N-ε-tert-butoxycarbonyl-L-lysyl-L-tryptophanamide(compound 80; yield: 92.6 mg).

Step 5

N-α-[(S)-2-N′-{N-α-6-guanidinohexyl-L-tyrosyl}amino-3-(4-hydroxy)phenyl]propyl-L-lysyl-L-tryptophanamide

The compound 80 (92.6 mg, 0.08 mmol) was reacted in accordance with themethod for synthesizing the compound 20 to obtainN-α-[(S)-2-N′-[N″-6-guanidinohexyl-L-tyrosyl]amino-3-(4-hydroxy)phenyl]propyl-L-lysyl-L-tryptophanamide(compound 81; yield: 45.2 mg).

FAB MS [M+H]⁺=785

EXAMPLE 19N-α-6-Guanidinohexyl-L-tyrosyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide

Step 1

N-[(R)-1-(2-Napthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide

N-α-9-Fluorenylmethoxycarbonyl-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-arginine(3.0 g, 4.53 mmol) and R-(+)-1-(2-naphthyl)ethylamine (775 mg, 4.53mmol) were reacted in accordance with the method for synthesizing thecompound 1 to obtainN-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide(compound 82; yield: 2.52 g).

Step 2

O-tert-Butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide

N-α-9-Fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine (310 mg, 0.67mmol) and the compound 82 (400 mg, 0.67 mmol) were reacted in accordancewith the method for synthesizing the compound 1 to obtainO-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide(compound 83; yield: 509 mg).

Step 3

N-α-[6-(2,3-di-tert-Butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide

The compound 79 (55.0 mg, 0.10 mmol) and the compound 83 (77.2 mg, 0.10mmol) were reacted in accordance with the method for synthesizing thecompound 73 to obtainN-α-[6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide(compound 84; yield: 108 mg).

Step 4

N-α-6-Guanidinohexyl-L-tyrosyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide

The compound 84 (108 mg, 0.08 mmol) was reacted in accordance with themethod for synthesizing the compound 7 to obtainN-α-6-guanidinohexyl-L-tyrosyl-L-tyrosyl-[N-(R)-1-(2-naphthyl)ethyl]-L-argininamide(compound 85; yield: 54.7 mg).

FAB MS [M+H]⁺=795

EXAMPLE 20N-α-6-guanidinohexyl-L-tyrosyl-L-3-(2-naphthyl)-alanyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide

Step 1

L-3-(2-Naphthyl)-alanyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide

N-α-9-Fluorenylmethoxycarbonyl-L-3-(2-naphthyl)-alanine (295 mg, 0.67mmol) and the compound 82 (400 mg, 0.67 mmol) were reacted in accordancewith the method for synthesizing the compound 1 to obtainL-3-(2-naphthyl)-alanyl-[N-(R)-1-(2-naphthyl)ethyl]-(N-ω-2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide(compound 86; yield: 500 mg).

Step 2

N-α-[6-(2,3-di-tert-Butoxycarbonylguanidino)hexyl]-O-tert-butyl-L-tyrosyl-L-3-(2-naphthyl)-alanyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide

The compound 79 (61.1 mg, 0.11 mmol) and the compound 86 (83.5 mg, 0.11mmol) were reacted in accordance with the method for synthesizing thecompound 73 to obtainN-α-[6-(2,3-di-tert-butoxycarbonylguanidino)hexyl]-(O-tert-butyl)-L-tyrosyl-L-3-(2-naphthyl)-alanyl-[N-(R)-1-(2-naphthyl)ethyl]-(N-ω-2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide(compound 87; yield: 114 mg).

Step 3

N-α-6-Guanidinohexyl-L-tyrosyl-L-3-(2-naphthyl)-alanyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide

The compound 87 (114 mg, 0.08 mmol) was reacted in accordance with themethod for synthesizing the compound 7 to obtainN-α-6-guanidinohexyl-L-tyrosyl-L-3-(2-naphthyl)-alanyl-[N-(R)-1-(2-naphthyl)ethyl]-L-argininamide(compound 88; yield: 72.2 mg).

FAB MS [M+H]⁺=829

EXAMPLE 21N-α-6-Guanidinohexyl-L-3-(1-naphthyl)-alanyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide

Step 1

L-3-(1-Naphthyl)-alanyl-O-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide

N-α-9-Fluorenylmethoxycarbonyl-L-3-(1-naphthyl)-alanine (161 mg, 0.37mmol) and the compound 83 (300 mg, 0.37 mmol) were reacted in accordancewith the method for synthesizing the compound 1 to obtainL-3-(1-naphthyl)-alanyl-O-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide(compound 89; yield: 365 mg).

Step 2

N-α-[6-(2,3-di-tert-Butoxycarbonyl)guanidinohexyl]-L-3-(1-naphthyl)-alanyl-O-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide

A crude product of the compound 5 (63 mg) and the compound 89 (150 mg,0.15 mmol) were reacted in accordance with the method for synthesizingthe compound 6 to obtainN-α-[6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl]-L-3-(1-naphthyl)-alanyl-(O-tert-butyl)-L-tyrosyl-[N-(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide(compound 90; yield: 101 mg).

Step 3

N-α-6-Guanidinohexyl-L-3-(1-naphthyl)-alanyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide

The compound 90 (101 mg, 0.08 mmol) was reacted in accordance with themethod for synthesizing the compound 7 to obtainN-α-6-guanidinohexyl-L-3-(1-naphthyl)-alanyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide(compound 91; yield: 56.6 mg).

FAB MS [M+H]⁺=829

EXAMPLE 22N-α-4-Guanidinobutylcarbamoyl-L-tyrosyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide

Step 1

4-(2,3-di-tert-Butoxycarbonyl)guanidino-1-butylamine

1,4-Di-aminobutane (1.37 g, 15.5 mmol) was dissolved in methylenechloride (30 mL), combined with1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (1.50 g, 5.17mmol) and stirred overnight. The reaction solution was concentratedunder reduced pressure, and the residue was subjected to a columnchromatography to obtain4-(2,3-di-tert-butoxycarbonyl)guanidino-1-butylamine (compound 92;yield: 813 mg).

Step 2

N-α-[4-(2,3-di-tert-Butoxycarbonyl)guanidinobutylcarbamoyl]-O-tert-butyl-L-tyrosinebenzyl ester

Triphosgene (84.0 mg, 0.28 mmol) was dissolved in methylene chloride,combined under argon flow with O-tert-butyl-L-tyrosine benzyl ester (250mg, 0.76 mg) and N,N-diisopropylethylamine (146 μM 0.84 mmol) andstirred at room temperature for 2.5 minutes. This reaction solution wascombined with the compound 92 (278 mg, 0.84 mmol) andN,N-diisopropylethylamine (161 μL, 0.92 mmol) dissolved in methylenechloride (2 mL), and stirred at room temperature further for 10 minutes.After completion of the reaction, the mixture was extracted with ethylacetate, and washed with a 6% aqueous solution of potassium sulfate, asaturated aqueous solution of sodium hydrogen carbonate, a saturatedbrine and water. The organic layer was dried over sodium sulfate, madefree of solids by filtration through a cotton plug, and washed withethyl acetate. The filtrate and the wash were combined and concentratedunder reduced pressure. The resultant residue was subjected to a columnchromatography to obtainN-α-[4-(2,3-di-tert-butoxycarbonyl)guanidinobutylcarbamoyl]-O-tert-butyl-L-tyrosinebenzyl ester (compound 93; yield: 105 mg).

Step 3

N-α-[4-(2,3-di-tert-Butoxycarbonyl)guanidinobutylcarbamoyl]-O-tert-butyl-L-tyrosine

The compound 93 (105 mg, 0.15 mmol) was reacted in accordance with themethod for synthesizing the compound 58 to obtainN-α-[4-(2,3-di-tert-butoxycarbonyl)guanidinobutylcarbamoyl]-(O-tert-butyl)-L-tyrosine(compound 94; yield: 90.1 mg).

Step 4

N-α-[4-(2,3-di-tert-Butoxycarbonyl)quanidinobutylcarbamoyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide

The compound 83 (123 mg, 0.15 mmol) and the compound 94 (90.1 mg, 0.15mmol) were reacted in accordance with the method for synthesizing thecompound 73 to obtainN-α-[4-(2,3-di-tert-butoxycarbonyl)guanidinobutylcarbamoyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide(compound 95; yield: 157 mg).

Step 5

N-α-4-Guanidinobutylcarbamoyl-L-tyrosyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide

The compound 95 (157 mg, 0.11 mmol) was reacted in accordance with themethod for synthesizing the compound 7 to obtainN-α-4-guanidinobutylcarbamoyl-L-tyrosyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide(compound 96; yield: 79.0 mg).

FAB MS [M+H]⁺=810

EXAMPLE 23N-α-6-Guanidinopentyl-L-tyrosyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide

Step 1

6-(2,3-di-tert-Butoxycarbonyl)guanidino-1-pentanol

5-Amino-1-pentanol (1.00 g, 9.7 mmol) was reacted in accordance with themethod for synthesizing the compound 4 to obtain6-(2,3-di-tert-butoxycarbonyl)guanidino-1-pentanol (compound 97; yield:3.21 mg).

Step 2

6-(2,3-di-tert-Butoxycarbonyl)guanidino-1-pentanal

The compound 97 (100 mg, 0.29 mmol) was reacted in accordance with themethod for synthesizing the compound 5 to obtain a crude product of6-(2,3-di-tert-butoxycarbonyl)guanidino-1-pentanal (compound 98) (95.0mg).

Step 3

O-tert-Butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide

N-α-9-Fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine (226 mg, 0.49mmol) and the compound 83 (400 mg, 0.49 mmol) were reacted in accordancewith the method for synthesizing the compound 1 to obtainO-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide(compound 99; yield: 495 mg).

Step 4

N-α-[6-(2,3-di-tert-Butoxycarbonylguanidino)pentyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide

A crude product of the compound 98 (95 mg) and the compound 99 (150 mg,0.15 mmol) were reacted in accordance with the method for synthesizingthe compound 6 to obtainN-α-[6-(2,3-di-tert-butoxycarbonylguanidino)pentyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide(compound 100; yield: 101 mg).

Step 5

N-α-6-Guanidinopentyl-L-tyrosyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide

The compound 100 (101 mg, 0.07 mmol) was reacted in accordance with themethod for synthesizing the compound 7 to obtainN-α-6-guanidinopentyl-L-tyrosyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide(compound 101; yield: 57.2 mg).

FAB MS [M+H]⁺=781

EXAMPLE 24N-α-5-Guanidinopentylyl-L-tyrosyl-L-tyrosyl-L-arginyl-L-tryptophanamide

Step 1

5-Amino-n-valeric acid methyl ester

Methanol (15 mL) was cooled to 0° C., combined with thionyl chloride(1.25 mL, 17.1 mmol) and stirred further for 30 minutes. This reactionsolution was combined with 5-amino-n-valeric acid (500 mg, 4.3 mmol) andstirred at room temperature overnight. After completion of the reaction,the mixture was concentrated under reduced pressure to obtain a residue,which was dissolved in methylene chloride (10 mL), combined with1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (1.85 g, 6.4mmol) and stirred overnight. The reaction solution was concentratedunder reduced pressure, and the residue was subjected to a columnchromatography to obtain 5-amino-n-valeric acid methyl ester (compound102; yield: 865 mg).

Step 2

5-(2,3-di-tert-Butoxycarbonyl)guanidinovaleric acid

The compound 102 (865 mg, 2.32 mmol) was dissolved in a mixture oftetrahydrofuran (7 mL), methanol (3 mL) and water (2 mL), combined withlithium hydroxide monohydrate (300 mg, 7.15 mmol) and stirred at roomtemperature for 30 minutes. After completion of the reaction, themixture was concentrated under reduced pressure and the resultantresidue was extracted with ethyl acetate, and washed with a 6% aqueoussolution of potassium hydrogen sulfate, a saturated brine and water. Theorganic layer was dried over sodium sulfate, made free of solids byfiltration through a cotton plug, and washed with ethyl acetate. Thefiltrate and the wash were combined and concentrated under reducedpressure to obtain 5-(2,3-di-tert-butoxycarbonyl)guanidinovaleric acid(compound 103; yield: 826 mg).

Step 3

N-α-[5-(2,3-di-tert-Butoxycarbonyl)guanidinopentylyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide

The compound 99 (115 mg, 0.11 mmol) and the compound 103 (52 mg, 0.15mmol) were reacted in accordance with the method for synthesizing thecompound 73 to obtainN-α-[5-(2,3-di-tert-butoxycarbonyl)guanidinopentylyl]-O-tert-butyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide(compound 104; yield: 81.2 mg).

Step 4

N-α-5-Guanidinopentylyl-L-tyrosyl-L-tyrosyl-L-arginyl-L-tryptophanamide

The compound 104 (81.2 mg, 0.06 mmol) was reacted in accordance with themethod for synthesizing the compound 7 to obtainN-α-5-guanidinopentylyl-L-tyrosyl-L-tyrosyl-L-arginyl-L-tryptophanamide(compound 105; yield: 41.3 mg).

FAB MS [M+H]⁺=781

EXAMPLE 25N-α-6-Guanidinohexyl-3,5-dimethyl-L-tyrosyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide

Step 1

3,5-Dimethyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide

N-α-9-Fluorenylmethoxycarbonyl-3,5-dimethyl-L-tyrosine (160 mg, 0.37mmol) and the compound 83 (300 mg, 0.37 mmol) were reacted in accordancewith the method for synthesizing the compound 1 to obtain3,5-dimethyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide(compound 106; yield: 350 mg).

Step 2

N-α-[6-(2,3-di-tert-Butoxycarbonyl)guanidinohexyl]-3,5-dimethyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide

A crude product of the compound 5 (89 mg) and the compound 106 (150 mg,0.15 mmol) were reacted in accordance with the method for synthesizingthe compound 6 to obtainN-α-[6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl]-3,5-dimethyl-L-tyrosyl-O-tert-butyl-L-tyrosyl-AT-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide(compound 107; yield: 87.2 mg).

Step 3

N-α-6-Guanidinohexyl-3,5-dimethyl-L-tyrosyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide

The compound 107 (87.2 mg, 0.06 mmol) was reacted in accordance with themethod for synthesizing the compound 7 to obtainN-α-6-guanidinohexyl-3,5-dimethyl-L-tyrosyl-L-tyrosyl-N[(R)-1-(2-naphthyl)ethyl]-L-argininamide (compound 108; yield: 53.1 mg).

FAB MS [M+H]⁺=823

EXAMPLE 26N-α-6-Guanidinohexyl-L-tyrosyl-3,5-dimethyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide

Step 1

3,5-Dimethyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide

N-α-9-Fluorenylmethoxycarbonyl-3,5-dimethyl-L-tyrosine (200 mg, 0.46mmol) and the compound 82 (275 mg, 0.46 mmol) were reacted in accordancewith the method for synthesizing the compound 1 to obtain3,5-dimethyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide(compound 109; yield: 354 mg).

Step 2

O-tert-Butyl-L-tyrosyl-3,5-dimethyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide

N-α-9-Fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine (95 mg, 0.21mmol) and the compound 109 (162 mg, 0.21 mmol) were reacted inaccordance with the method for synthesizing the compound 1 to obtainO-tert-butyl-L-tyrosyl-3,5-dimethyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide(compound 110; yield: 196 mg).

Step 3

N-α-[6-(2,3-di-tert-Butoxycarbonyl)guanidinohexyl]-O-tert-butyl)-L-tyrosyl-3,5-dimethyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide

A crude product of the compound 5 (124 mg) and the compound 110 (192 mg,0.19 mmol) were reacted in accordance with the method for synthesizingthe compound 6 to obtainN-α-[6-(2,3-di-tert-butoxycarbonyl)guanidinohexyl]-O-tert-butyl-L-tyrosyl-3,5-dimethyl-L-tyrosyl-N-[(R)-1-(2-naphtyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide(compound 111; yield: 184 mg).

Step 4

N-α-6-Guanidinohexyl-L-tyrosyl-3,5-dimethyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide

The compound 111 (184 mg, 0.14 mmol) was reacted in accordance with themethod for synthesizing the compound 7 to obtainN-α-6-guanidinohexyl-L-tyrosyl-3,5-dimethyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide(compound 112; yield: 91.8 mg).

FAB MS [M+H]⁺=823

EXAMPLE 27N-α-6-Guanidinohexyl-3,5-dimethyl-L-tyrosyl-3,5-dimethyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide

Step 1

3,5-Dimethyl-L-tyrosyl-3,5-dimethyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide

N-α-9-Fluorenylmethoxycarbonyl-3,5-dimethyl-L-tyrosine (96.2 mg, 0.22mmol) and the compound 109 (175 mg, 0.22 mmol) were reacted inaccordance with the method for synthesizing the compound 1 to obtain3,5-dimethyl-L-tyrosyl-3,5-dimethyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide(compound 113; yield: 210 mg).

Step 2

N-α-[6-(2,3-di-tert-Butoxycarbonylguanidino)hexyl]-3,5-dimethyl-L-tyrosyl-3,5-dimethyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide

A crude product of the compound 5 (108 mg, 0.30 mmol) and the compound113 (210 mg, 0.22 mmol) were reacted in accordance with the method forsynthesizing the compound 6 to obtainN-α-[6-(2,3-di-tert-butoxycarbonylguanidino)hexyl-3,5-dimethyl-L-tyrosyl-3,5-dimethyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-N-ω-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-L-argininamide(compound 114; yield: 216 mg).

Step 3

N-α-6-Guanidinohexyl-3,5-dimethyl-L-tyrosyl-3,5-dimethyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide

The compound 114 (208 mg, 0.16 mmol) was reacted in accordance with themethod for synthesizing the compound 7 to obtainN-α-6-guanidinohexyl-3,5-dimethyl-L-tyrosyl-3,5-dimethyl-L-tyrosyl-N-[(R)-1-(2-naphthyl)ethyl]-L-argininamide(compound 115; yield: 122 mg).

FAB MS [M+H]⁺=851

Test Example 1 Nociceptin Receptor Binding Test

A cell membrane suspension obtained from a human nociceptin-expressingcell was adjusted at a membrane protein level of 5 to 10 μg/mL in a Trisbuffer [50 mM Tris-HCl (pH 7.8), 5 mM MgCl₂, 1 mM EGTA, 0.1% BSA]. Tothis suspension, [³H] nociceptin (diluted to the final concentration of0.08 nM in the Tris buffer) and a test substance were added, and themixture was incubated at 25° C. for 60 minutes. Using a cell harvesterand a washing solution [50 mM Tris-HCl (pH 7.8), 4° C.], the membranewas recovered onto the GF/B filter which had been pretreated with 0.3%PEI, and washed further 4 times. The filter was transferred into a vial,to which a scintillator was added, and then the radioactivity wasmeasured using a liquid scintillation counter. A non-specific bindingwas regarded as a binding in the presence of 10 μM nociceptin, and thedifference between the total binding and the non-specific binding wasregarded as the specific binding. Based on the % binding inhibition inthe presence of a test substance, the IC₅₀ was obtained and employedtogether with the Kd value of the [³H] nociceptin to calculate the Kivalue of the test substance (mol/L; hereinafter referred to as N value).

The results are shown in Table 1.

Test Example 2 μReceptor Binding Test

A human μ receptor-expressing cell membrane preparation (ReceptorBiology) was adjusted at the membrane protein level of 8.5 μg/mL in aTris buffer [50 mM Tris-HCl (pH 7.8), 5 mM MgCl₂, 1 mM EGTA, 0.1% BSA].To this suspension, [³H] diprenorphine (diluted to the finalconcentration of 0.13 nM in the Tris buffer) and a test substance wereadded, and the mixture was incubated at 25° C. for 90 minutes. Using acell harvester and a washing solution [50 mM Tris-HCl (pH 7.8), 4° C.],the membrane was recovered onto the GF/B filter which had beenpretreated with 0.3% PEI, and washed further 4 times. The filter wastransferred into a vial, to which a scintillator was added, and then theradioactivity was measured using a liquid scintillation counter. Anon-specific binding was regarded as a binding in the presence of 100 μMnaloxone, and the difference between the total binding and thenon-specific binding was regarded as the specific binding. Based on the% binding inhibition in the presence of a test substance, the IC₅₀ wasobtained and employed together with the Kd value of the [³H]diprenorphine to calculate the Ki value of the test substance (mol/L;hereinafter referred to as M value). The M value was divided by the Nvalue obtained in Test Example 1 to judge the selectivity of thereceptor binding of the test substance.

The results are shown in Table 1.

TABLE 1 Results of μ nociceptin receptor and receptor binding test Testcompound Ki for nociceptin Selectivity (Example receptor Ki for μreceptor (M value/ No.) (N value) (M value) N value) 1 4.3 × 10⁻¹⁰(mol/L) 4.0 × 10⁻⁸ (mol/L) 93 23 1.8 × 10⁻⁹ (mol/L) 5.9 × 10⁻⁸ (mol/L)32 25 9.0 × 10⁻¹⁰ (mol/L) 1.4 × 10⁻⁸ (mol/L) 15 27 6.0 × 10⁻¹⁰ (mol/L)1.0 × 10⁻⁸ (mol/L) 17

Based on the results shown in Table 1, each compound of the presentinvention was proven to be capable of binding the human nociceptinreceptor.

Test Example 3 Mouse Formalin Test

Male mice (ddY; 4 to 5 weeks old) were kept at a room temperature of 21to 25° C. and a humidity of 45 to 65% in a cage having a 12-hourlight/12-hour dark cycle while being fed with feed and water ad libitum,whereby being acclimatized for a period of 1 week or longer. 6 Animalsin each group were employed.

The compound of Example 1 was dissolved in physiological saline. Eachmouse was placed in a cylindrical tube whose diameter was about 4 cm,immobilized at its tail, and a 27G needle connected to a 1 mL syringewas inserted into its tail vein, via which 0.1 mL/10 g body weight ofthe drug solution was administered rapidly. In a control group,physiological saline was administered. After administration, anabsorbent cotton was used for hemostasis, and the animal was returned tothe observation cage. The dose of the compound of Example 1 was 1 mg or3 mg per 1 kg body weight of each mouse.

Subsequently, each mouse was acclimatized sufficiently to theobservation cage, and then placed in a retainer for the drugadministration. 20 μL of a 1% formalin solution was subcutaneouslyadministered into the plantar region of the hindpaw, and the mouse wasreturned to the observation cage, and examined for the duration of anyaversive behavior such as licking or biting the administered hindpawextremity over a period of 30 minutes using a stopwatch.

The results are shown in Table 2.

TABLE 2 Results of formalin test Time after formalin Duration ofaversive behavior administration (sec) (min) Control 1 mg/kg Group 3mg/kg Group  0 to 10 128.3 80.8** 41.00** (13.1) (9.3) (7.4) 10 to 30261.0 163.8 112.8** (31.7) (37.8) (16.5) Figure in ( ) represents astandard error. **P < 0.01 compared with control by Dunnett's multiplecomparison

Based on the results of the tests described above, each inventivecompound was proven to be capable of binding a human nociceptin receptorcell selectively, and to have an analgesic effect.

INDUSTRIAL APPLICABILITY

A compound according to the present invention is a nociceptin receptor(ORL-1) agonist and useful as an analgesic or anxiolytic agent.

1. A compound of formula (1) or a pharmaceutically acceptable saltthereof:

in which A is alkylene, formula (2) or formula (3):

X and Y are the same or different and each represents —CONH— or —CH₂NH—;R¹, R² and R³ are the same or different and each represents alkyl, arylor heteroaryl, wherein said alkyl aryl and heteroaryl are optionallysubstituted by 1 to 3 same or different substituents selected from thegroup consisting of halogen, nitro, hydroxy, cyano, carbamoyl, alkyl,aryl optionally substituted by hydroxy, heteroaryl optionallysubstituted by hydroxy, alkenyl, alkynyl, alkoxylcarbonyl, acyl, amino,monoalkylamino, dialkylamino, alkoxy, aryloxy, arylalkyloxy, alkylthio,arylalkylthio, heteroarylalkylthio, arylsulfonyl, alkylsulfonyl andguanidino; and Z represents —CON(R⁴)R⁵ or —CH₂N(R⁴)R⁵ wherein R⁴ and R⁵are the same or different and each represents hydrogen, alkyl, aryl orheteroaryl, wherein said alkyl, aryl and heteroaryl are optionallysubstituted by 1 to 3 same or different substituents selected from thegroup consisting of halogen, nitro, hydroxy, carboxy, cyano, carbamoyl,alkyl, aryl optionally substituted by hydroxy, heteroaryl optionallysubstituted by hydroxy, alkenyl, alkynyl, alkoxycarbonyl, acyl, amino,monoalkylamino, dialkylamino, alkoxy, aryloxy, arylalkyloxy, alkylthio,arylalkylthio, heteroarylalkylthio, arylsulfonyl, alkylsulfonyl,guanidino, N-monoalkylcarbamoyl, N,N-dialkylcarbamoyl and hydroxymethyl.2. A compound of formula (1) or a pharmaceutically acceptable saltthereof:

in which A is alkylene, formula (2) or formula (3):

X and Y are the same or different and each represents —CONH— or —CH₂NH—;Z represents —CON(R⁴)R⁵ or —CH₂N(R⁴)R⁵ wherein R⁴ and R⁵ are the same ordifferent and each represents hydrogen, alkyl, aryl or heteroaryl,wherein said alkyl, aryl and heteroaryl are optionally substituted by 1to 3 same or different substituents selected from the group consistingof halogen, nitro, hydroxy, carboxy, cyano, carbamoyl, alkyl, aryloptionally substituted by hydroxy, heteroaryl optionally substituted byhydroxy, alkenyl, alkynyl, alkoxycarbonyl, acyl, amino, monoalkylamino,dialkylamino, alkoxy, aryloxy, arylalkyloxy, alkylthio, arylalkylthio,heteroarylalkylthio, arylsulfonyl, alkylsulfonyl, guanidino,N-monoalkylcarbamoyl, N,N-dialkylcarbamoyl and hydroxymethyl; R¹ isoptionally substituted benzyl or naphthylmethyl; R² is 4-hydroxybenzyl;and R³ is 4-aminobutyl or 3-guandinopropyl.
 3. A compound of formula (1)or pharmaceutically acceptable salt thereof according to claim 1,wherein: A is pentamethylene, hexamethylene or heptamethylene; R¹ isoptionally substituted benzyl or naphthylmethyl; R² is 4-hydroxybenzyl;R³ is 4-aminobutyl or 3 guanidinopropyl; and Z is —CONH—CH(R⁶)R⁷, inwhich R⁶ represents aryl or arylalkyl and R⁷ represents hydrogen,carboxy, carbamoyl, hydroxymethyl or aryl.
 4. A pharmaceuticalcomposition having as an active ingredient a compound of formula (1) orpharmaceutically acceptable salt thereof according to any one of claims1, 2 or
 3. 5. A nociceptin receptor agonist composition having as anactive ingredient a compound of formula (1) or a pharmaceuticallyacceptable salt thereof according to any one of claims 1, 2 or 3.